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    Clinical Trial Results:
    A 24 week treatment, multicenter, randomized, double blinded, double dummy, parallel-group, clinical trial evaluating the efficacy and safety of aclidinium bromide 400 μg/formoterol fumarate 12 μg fixed-dose combination BID compared with each monotherapy (aclidinium bromide 400 μg BID and formoterol fumarate 12 μg BID) and tiotropium 18 μg QD when administered to subjects with stable chronic obstructive pulmonary disease

    Summary
    EudraCT number
    2015-005444-33
    Trial protocol
    GB   HU   CZ   BG   ES   PL  
    Global end of trial date
    08 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jun 2018
    First version publication date
    06 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D6571C00001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02796677
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    Information Centre, AstraZeneca AB, Information Centre, AstraZeneca AB, +1 800 2369933, information.centre@astrazeneca.com
    Scientific contact
    Global Clinical Leader, AstraZeneca AB, +46 766 346712, 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
    08 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    For United States (US): To assess the bronchodilatory effect of Aclidinium bromide/Formoterol fumarate (AB/FF) 400/12 μg compared to each individual component when administered twice daily (BID) via inhalation to chronic obstructive pulmonary disease (COPD) subjects. Ffor Market Access: To assess the non-inferior bronchodilation of AB 400 μg BID as compared to Tiotropium (TIO) 18 μg once daily (QD) in COPD subjects.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation /Good Clinical Practice (GCP), applicable regulatory requirements and the AstraZeneca policy on Bioethics. Each subject was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study. Each subject was notified that they were free to discontinue from the study at any time and were given the opportunity to ask questions and allowed time to consider the information provided. Each subject provided signed and dated ICF before conducting any procedure specifically for the study. A copy of the signed informed consent form (ICF) was given to the subject. Any incentives for subjects who participated in the study as well as any provisions for subjects harmed as a consequence of study participation were described in the ICF that was approved by an Ethics Committe.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Jul 2016
    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
    United States: 699
    Country: Number of subjects enrolled
    Germany: 349
    Country: Number of subjects enrolled
    Poland: 124
    Country: Number of subjects enrolled
    Hungary: 116
    Country: Number of subjects enrolled
    Bulgaria: 106
    Country: Number of subjects enrolled
    Ukraine: 110
    Country: Number of subjects enrolled
    United Kingdom: 34
    Country: Number of subjects enrolled
    Czech Republic: 32
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Israel: 17
    Worldwide total number of subjects
    1594
    EEA total number of subjects
    768
    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)
    795
    From 65 to 84 years
    793
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    Study was conducted on subjects with stable COPD, in 11 countries: United States (US), Germany, Poland, Hungary, Bulgaria, Ukraine, United Kingdom (UK), Czech Republic, Spain, Israel & Russia (was not finally started).

    Pre-assignment
    Screening details
    Eligible subjects signed ICF; entered screening period (Run-in; 14 ± 3 days), inclusion/exclusion criteria were checked by medical & COPD history, physical examination, blood pressure, electrocardiogram, laboratory tests, concomitant drugs & COPD Assessment Test [CAT] & post-bronchodilator forced expiratory volume in 1 second [FEV1]

    Period 1
    Period 1 title
    Period 1: Overall Study
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Aclidinium bromide (AB)/Formoterol fumarate (FF) 400/12 μg
    Arm description
    Randomized subjects received AB 400 μg/FF 12 μg oral inhalation powder twice daily (BID) via dry powder inhaler (DPI).
    Arm type
    Experimental

    Investigational medicinal product name
    Aclidinium bromide/Formoterol fumarate
    Investigational medicinal product code
    Other name
    Pressair®/Genuair® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    AB/FF 400/12 μg inhalation powder twice daily (morning and evening) via DPI for 24 weeks

    Arm title
    AB 400 μg
    Arm description
    Randomized subjects received AB 400 μg oral inhalation powder BID via DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    Aclidinium bromide
    Investigational medicinal product code
    Other name
    Pressair®/Genuair® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    AB 400 μg inhalation powder twice daily (morning and evening) via DPI for 24 weeks

    Arm title
    FF 12 μg
    Arm description
    Randomized subjects received FF 12 μg oral inhalation powder BID via DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    Formoterol fumarate
    Investigational medicinal product code
    Other name
    Pressair®/Genuair® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    FF 12 μg inhalation powder twice daily (morning and evening) via DPI for 24 weeks

    Arm title
    Tiotropium (TIO) 18 μg
    Arm description
    Randomized subjects received TIO 18 μg oral inhalation powder in capsule BID via DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    HandiHaler® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    TIO 18 μg inhalation powder QD (morning) via DPI for 24 weeks

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pressair®/Genuair® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    TIO 18 μg inhalation powder twice daily (morning and evening) via DPI for 24 weeks

    Number of subjects in period 1
    Aclidinium bromide (AB)/Formoterol fumarate (FF) 400/12 μg AB 400 μg FF 12 μg Tiotropium (TIO) 18 μg
    Started
    317
    478
    320
    479
    Completed
    279
    405
    267
    405
    Not completed
    38
    73
    53
    74
         Progressive disease
    6
    15
    13
    18
         Protocol deviation
    7
    5
    4
    8
         Reason not mentioned
    2
    3
    -
    5
         Lack of efficacy
    7
    9
    14
    20
         Adverse event, non-fatal
    11
    22
    14
    14
         Consent withdrawn by subject
    4
    14
    6
    7
         Lost to follow-up
    1
    5
    2
    2
    Period 2
    Period 2 title
    Intent-to-treat (ITT) population
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AB/FF 400/12 μg
    Arm description
    Randomized subjects received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).
    Arm type
    Experimental

    Investigational medicinal product name
    Aclidinium bromide/Formoterol fumarate
    Investigational medicinal product code
    Other name
    Pressair®/Genuair® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    AB/FF 400/12 μg inhalation powder twice daily (morning and evening) via DPI for 24 weeks

    Arm title
    AB 400 μg
    Arm description
    Randomized subjects received AB 400 μg oral inhalation powder BID via DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    Aclidinium bromide
    Investigational medicinal product code
    Other name
    Pressair®/Genuair® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    AB 400 μg inhalation powder twice daily (morning and evening) via DPI for 24 weeks

    Arm title
    FF 12 μg
    Arm description
    Randomized subjects received FF 12 μg oral inhalation powder BID via DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    Formoterol fumarate
    Investigational medicinal product code
    Other name
    Pressair®/Genuair® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    FF 12 μg inhalation powder twice daily (morning and evening) via DPI for 24 weeks

    Arm title
    TIO 18 μg
    Arm description
    Randomized subjects received orally TIO 18 μg inhalation powder in capsule QD via DPI.
    Arm type
    Experimental

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    HandiHaler® Dry Powder Inhaler
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Oral use
    Dosage and administration details
    TIO 18 μg inhalation powder QD (morning) via DPI for 24 weeks

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Subject disposition (Period 1) data were presented for the randomized population (N = 1594). The baseline characteristics and endpoints data were presented for the safety population and Intent-to-treat population (ITT; Period 2), respectively; in these two population sets, the number of subjects (N) was 1583. Hence, period 2 (ITT) was mentioned as the baseline period.
    Number of subjects in period 2 [2]
    AB/FF 400/12 μg AB 400 μg FF 12 μg TIO 18 μg
    Started
    314
    475
    319
    475
    Completed
    314
    475
    319
    475
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: All screened subjects were mentioned in the worldwide population of the trial whereas subjects who received at least 1 dose of the investigational product were mentioned in the ITT population (baseline period). Non-eligible subjects were not randomized in the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AB/FF 400/12 μg
    Reporting group description
    Randomized subjects received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).

    Reporting group title
    AB 400 μg
    Reporting group description
    Randomized subjects received AB 400 μg oral inhalation powder BID via DPI.

    Reporting group title
    FF 12 μg
    Reporting group description
    Randomized subjects received FF 12 μg oral inhalation powder BID via DPI.

    Reporting group title
    TIO 18 μg
    Reporting group description
    Randomized subjects received orally TIO 18 μg inhalation powder in capsule QD via DPI.

    Reporting group values
    AB/FF 400/12 μg AB 400 μg FF 12 μg TIO 18 μg Total
    Number of subjects
    314 475 319 475 1583
    Age categorical
    Safety analysis set: Defined as all randomized subjects who took at least one dose of the study drug.
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    166 270 168 263 867
        From 65-84 years
    146 205 151 209 711
        85 years and over
    2 0 0 3 5
    Age Continuous
    Safety analysis set: Defined as all randomized subjects who took at least one dose of the study drug.
    Units: years
        arithmetic mean (standard deviation)
    64.4 ± 8.5 64.4 ± 8.1 64.7 ± 8.3 64.0 ± 8.6 -
    Sex: Female, Male
    Safety analysis set: Defined as all randomized subjects who took at least one dose of the study drug.
    Units: Subjects
        Female
    121 171 129 199 620
        Male
    193 304 190 276 963

    End points

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    End points reporting groups
    Reporting group title
    Aclidinium bromide (AB)/Formoterol fumarate (FF) 400/12 μg
    Reporting group description
    Randomized subjects received AB 400 μg/FF 12 μg oral inhalation powder twice daily (BID) via dry powder inhaler (DPI).

    Reporting group title
    AB 400 μg
    Reporting group description
    Randomized subjects received AB 400 μg oral inhalation powder BID via DPI.

    Reporting group title
    FF 12 μg
    Reporting group description
    Randomized subjects received FF 12 μg oral inhalation powder BID via DPI.

    Reporting group title
    Tiotropium (TIO) 18 μg
    Reporting group description
    Randomized subjects received TIO 18 μg oral inhalation powder in capsule BID via DPI.
    Reporting group title
    AB/FF 400/12 μg
    Reporting group description
    Randomized subjects received orally AB 400 μg/FF 12 μg inhalation powder twice daily (BID) via dry powder inhaler (DPI).

    Reporting group title
    AB 400 μg
    Reporting group description
    Randomized subjects received AB 400 μg oral inhalation powder BID via DPI.

    Reporting group title
    FF 12 μg
    Reporting group description
    Randomized subjects received FF 12 μg oral inhalation powder BID via DPI.

    Reporting group title
    TIO 18 μg
    Reporting group description
    Randomized subjects received orally TIO 18 μg inhalation powder in capsule QD via DPI.

    Subject analysis set title
    AB/FF 400/12 μg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Randomized subjects received orally AB 400 μg/FF 12 μg inhalation powder BID via DPI.

    Subject analysis set title
    AB 400 μg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ‌ Randomized subjects received AB 400 μg oral inhalation powder BID via DPI.

    Subject analysis set title
    AB 400 μg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    ‌ Randomized subjects received AB 400 μg oral inhalation powder BID via DPI.

    Subject analysis set title
    FF 12 μg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Randomized subjects received FF 12 μg oral inhalation powder BID via DPI.

    Subject analysis set title
    TIO 18 μg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Randomized subjects received orally TIO 18 μg inhalation powder in capsule QD via DPI.

    Subject analysis set title
    TIO 18 μg
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Randomized subjects received orally TIO 18 μg inhalation powder in capsule QD via DPI.

    Primary: Change from baseline in 1-hour morning post-dose dose forced expiratory volume in 1 second (FEV1) of AB/FF 400/12 μg compared to AB 400 μg at week 24

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    End point title
    Change from baseline in 1-hour morning post-dose dose forced expiratory volume in 1 second (FEV1) of AB/FF 400/12 μg compared to AB 400 μg at week 24
    End point description
    To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 at 1 hour post-dose of AB/FF 400/12 µg compared to AB 400 μg after administration of oral inhalation powder BID via DIP to subjects with COPD. Baseline was defined as the average of the two FEV1 values measured just prior to the administration of the first dose of investigational product (IP) at randomization Visit. If one of the two was missing, then the available one would be used as baseline value.
    End point type
    Primary
    End point timeframe
    At baseline 1-hour postdose and Week 24
    End point values
    AB/FF 400/12 μg AB 400 μg FF 12 μg TIO 18 μg
    Number of subjects analysed
    274
    398
    258
    400
    Units: Litres
        least squares mean (standard error)
    0.253 ± 0.013
    0.169 ± 0.011
    0.168 ± 0.013
    0.161 ± 0.011
    Statistical analysis title
    AB/FF 400/12 μg versus AB 400 μg
    Statistical analysis description
    Number of subjects analyzed were 274 in AB/FF 400/12 μg arm and 398 in AB 400 μg arm.
    Comparison groups
    AB/FF 400/12 μg v AB 400 μg
    Number of subjects included in analysis
    672
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed model for repeated measures
    Parameter type
    LS mean difference
    Point estimate
    0.084
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.051
         upper limit
    0.117

    Primary: Change from baseline in morning predose (trough) FEV1 of AB/FF 400/12 μg compared to FF 12 μg at week 24

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    End point title
    Change from baseline in morning predose (trough) FEV1 of AB/FF 400/12 μg compared to FF 12 μg at week 24
    End point description
    To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough) of AB/FF 400/12 µg compared to FF 12 μg after administration of oral inhalation powder BID via DPI to subjects with COPD. Morning pre-dose (trough) FEV1 was defined as the average of the corresponding -30 minute and 0 minute before the morning study medication administration at Week 24. If one time-point was missing then the available one would be used as morning pre-dose.
    End point type
    Primary
    End point timeframe
    At baseline morning predose and Week 24
    End point values
    AB/FF 400/12 μg AB 400 μg FF 12 μg TIO 18 μg
    Number of subjects analysed
    274
    401
    259
    401
    Units: Litres
        least squares mean (standard error)
    0.080 ± 0.014
    0.066 ± 0.012
    0.025 ± 0.014
    0.060 ± 0.012
    Statistical analysis title
    AB/FF 400/12 μg versus FF 12 μg
    Statistical analysis description
    Number of subjects analyzed were 274 in AB/FF 400/12 μg arm and 259 in AB 400 μg arm.
    Comparison groups
    AB/FF 400/12 μg v FF 12 μg
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009
    Method
    Mixed model for repeated measures
    Parameter type
    LS mean difference
    Point estimate
    0.055
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.023
         upper limit
    0.088

    Primary: Change from baseline in morning predose (trough) FEV1 at week 24 comparing AB 400 μg versus TIO 18 μg to demonstrate non-inferiority

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    End point title
    Change from baseline in morning predose (trough) FEV1 at week 24 comparing AB 400 μg versus TIO 18 μg to demonstrate non-inferiority
    End point description
    To assess the non-inferior bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough) of AB 400 µg BID compared to TIO 18 μg QD after administration of oral inhalation powder via DPI to subjects with COPD.
    End point type
    Primary
    End point timeframe
    At baseline morning predose and Week 24
    End point values
    AB 400 μg TIO 18 μg
    Number of subjects analysed
    369
    369
    Units: Litres
        least squares mean (standard error)
    0.064 ± 0.013
    0.057 ± 0.013
    Statistical analysis title
    AB 400 μg versus TIO 18 μg
    Statistical analysis description
    Number of subjects analyzed were 369 in AB 400 μg arm and 369 in TIO 18 μg arm.
    Comparison groups
    AB 400 μg v TIO 18 μg
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.6377
    Method
    Mixed model for repeated measures
    Parameter type
    LS mean difference
    Point estimate
    0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.021
         upper limit
    0.035
    Notes
    [1] - Non-inferiority was established by showing that the lower bound of the two-sided 95% confidence interval for change from baseline in morning pre-dose (trough) FEV1 at week 24 when compared AB 400 μg versus TIO 18 μg was higher than -50 mL (non-inferiority limit).

    Secondary: Change from baseline in normalized Area under curve 3 hours post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg compared to AB 400 μg and and FF 12 μg at Week 24

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    End point title
    Change from baseline in normalized Area under curve 3 hours post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg compared to AB 400 μg and and FF 12 μg at Week 24
    End point description
    To assess the bronchodilatory effect by evaluating the mean changes from baseline in normalized AUC0-3/3h FEV1 of AB/FF 400/12 µg compared to AB 400 μg and and FF 12 μg after administration of oral inhalation powder BID via DPI to subjects with COPD.
    End point type
    Secondary
    End point timeframe
    At baseline and Week 24
    End point values
    AB/FF 400/12 μg AB 400 μg FF 12 μg TIO 18 μg
    Number of subjects analysed
    273
    396
    257
    398
    Units: Litres
        least squares mean (standard error)
    0.237 ± 0.013
    0.162 ± 0.010
    0.149 ± 0.013
    0.151 ± 0.010
    Statistical analysis title
    AB/FF 400/12 μg versus AB 400 μg
    Statistical analysis description
    Number of subjects analyzed were 273 in AB/FF 400/12 μg arm and 396 in AB 400 μg arm.
    Comparison groups
    AB/FF 400/12 μg v AB 400 μg
    Number of subjects included in analysis
    669
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed model for repeated measures
    Parameter type
    LS mean difference
    Point estimate
    0.075
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.043
         upper limit
    0.107
    Statistical analysis title
    AB/FF 400/12 μg versus FF 12 μg
    Statistical analysis description
    Number of subjects analyzed were 273 in AB/FF 400/12 μg arm and 257 in FF 12 μg arm.
    Comparison groups
    AB/FF 400/12 μg v FF 12 μg
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed model for repeated measures
    Parameter type
    LS mean difference
    Point estimate
    0.087
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.052
         upper limit
    0.122

    Secondary: Responder (number [%] of subjects) analysis of St. George's Respiratory Questionnaire (SGRQ) total score with AB/FF 400/12 μg versus AB 400 μg and FF 12 μg.

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    End point title
    Responder (number [%] of subjects) analysis of St. George's Respiratory Questionnaire (SGRQ) total score with AB/FF 400/12 μg versus AB 400 μg and FF 12 μg.
    End point description
    SGRQ was a standardized self-completed tool used to measure impaired health and perceived well-being (“quality of life”) in respiratory diseases. The questionnaire contained 50 items divided into 3 (symptoms, activity and impacts) dimensions. Each of the 3 dimensions of the questionnaire was scored separately in the range from 0 to 100% (score 0 - no impairment and higher score - poorer health). A summary score utilized responses of all items as the total SGRQ score. SGRQ responders were those with a decrease in SGRQ total score of at least 4 units (criterion for minimal meaningful improvement) from baseline.
    End point type
    Secondary
    End point timeframe
    At baseline and Week 24
    End point values
    AB/FF 400/12 μg AB 400 μg FF 12 μg TIO 18 μg
    Number of subjects analysed
    314
    475
    319
    475
    Units: Percentages
        Yes|
    130
    188
    128
    197
        Percentages of "Yes"|
    48
    49
    50
    51
        No|
    140
    195
    130
    192
        Percentages of "No"|
    52
    51
    50
    49
    Statistical analysis title
    AB/FF 400/12 μg versus AB 400 μg
    Statistical analysis description
    Number of subjects analyzed were 314 in AB/FF 400/12 μg arm and 475 in AB 400 μg arm.
    Comparison groups
    AB/FF 400/12 μg v AB 400 μg
    Number of subjects included in analysis
    789
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8714
    Method
    Logistic random-effect model
    Parameter type
    Odds ratio
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.51
    Statistical analysis title
    AB/FF 400/12 μg versus FF 12 μg
    Statistical analysis description
    Number of subjects analyzed were 314 in AB/FF 400/12 μg arm and 319 in AB 400 μg arm.
    Comparison groups
    AB/FF 400/12 μg v FF 12 μg
    Number of subjects included in analysis
    633
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8873
    Method
    Logistic random-effect model
    Parameter type
    Odds ratio
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.59
         upper limit
    1.58

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From time of signature of the ICF throughout the treatment period and including the follow-up period (2 weeks after the last study drug administration)
    Adverse event reporting additional description
    An adverse event – An undesirable medical condition/deterioration of pre-existing medical condition following/during exposure to pharmaceutical product, whether/not considered causally related to product. An undesirable medical condition - symptoms (e.g. nausea), signs (e.g. tachycardia)/ abnormal investigation results (e.g. laboratory findings)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    AB/FF 400/12 μg
    Reporting group description
    Randomized subjects received orally AB 400 μg/FF 12 μg inhalation powder BID via DPI.

    Reporting group title
    AB 400 μg
    Reporting group description
    Randomized subjects received AB 400 μg oral inhalation powder BID via DPI.

    Reporting group title
    FF 12 μg
    Reporting group description
    Randomized subjects received orally FF 12 μg inhalation powder BID via DPI.

    Reporting group title
    TIO 18 μg
    Reporting group description
    Randomized subjects received orally TIO 18 μg inhalation powder in capsule QD via DPI.

    Serious adverse events
    AB/FF 400/12 μg AB 400 μg FF 12 μg TIO 18 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 314 (7.32%)
    41 / 475 (8.63%)
    22 / 319 (6.90%)
    37 / 475 (7.79%)
         number of deaths (all causes)
    1
    1
    4
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal meningioma benign
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma stage IV
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arterial bypass occlusion
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc injury
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery stenosis
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 314 (0.00%)
    2 / 475 (0.42%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 314 (0.00%)
    2 / 475 (0.42%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    3 / 475 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cor pulmonale chronic
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Atrial tachycardia
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    7 / 314 (2.23%)
    11 / 475 (2.32%)
    10 / 319 (3.13%)
    14 / 475 (2.95%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 11
    0 / 10
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 475 (0.21%)
    1 / 319 (0.31%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Polycythaemia
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar stroke
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 475 (0.21%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 314 (0.32%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypercalcaemia of malignancy
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 314 (1.27%)
    3 / 475 (0.63%)
    1 / 319 (0.31%)
    2 / 475 (0.42%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 314 (0.32%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    1 / 319 (0.31%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 314 (0.00%)
    1 / 475 (0.21%)
    0 / 319 (0.00%)
    0 / 475 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis viral
         subjects affected / exposed
    0 / 314 (0.00%)
    0 / 475 (0.00%)
    0 / 319 (0.00%)
    1 / 475 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    AB/FF 400/12 μg AB 400 μg FF 12 μg TIO 18 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    173 / 314 (55.10%)
    222 / 475 (46.74%)
    178 / 319 (55.80%)
    241 / 475 (50.74%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 314 (2.23%)
    8 / 475 (1.68%)
    9 / 319 (2.82%)
    7 / 475 (1.47%)
         occurrences all number
    7
    8
    10
    9
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary
         subjects affected / exposed
    49 / 314 (15.61%)
    79 / 475 (16.63%)
    58 / 319 (18.18%)
    61 / 475 (12.84%)
         occurrences all number
    60
    90
    74
    70
    Dyspnoea
         subjects affected / exposed
    6 / 314 (1.91%)
    13 / 475 (2.74%)
    6 / 319 (1.88%)
    12 / 475 (2.53%)
         occurrences all number
    6
    18
    7
    12
    Cough
         subjects affected / exposed
    6 / 314 (1.91%)
    7 / 475 (1.47%)
    4 / 319 (1.25%)
    17 / 475 (3.58%)
         occurrences all number
    7
    7
    4
    19
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 314 (5.10%)
    19 / 475 (4.00%)
    17 / 319 (5.33%)
    25 / 475 (5.26%)
         occurrences all number
    27
    20
    19
    31
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 314 (1.91%)
    9 / 475 (1.89%)
    7 / 319 (2.19%)
    7 / 475 (1.47%)
         occurrences all number
    6
    9
    7
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 314 (4.78%)
    7 / 475 (1.47%)
    8 / 319 (2.51%)
    7 / 475 (1.47%)
         occurrences all number
    22
    7
    12
    8
    Arthralgia
         subjects affected / exposed
    8 / 314 (2.55%)
    4 / 475 (0.84%)
    3 / 319 (0.94%)
    8 / 475 (1.68%)
         occurrences all number
    9
    4
    4
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    36 / 314 (11.46%)
    47 / 475 (9.89%)
    39 / 319 (12.23%)
    64 / 475 (13.47%)
         occurrences all number
    42
    56
    45
    67
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 314 (2.55%)
    13 / 475 (2.74%)
    7 / 319 (2.19%)
    17 / 475 (3.58%)
         occurrences all number
    9
    15
    7
    21
    Sinusitis
         subjects affected / exposed
    8 / 314 (2.55%)
    10 / 475 (2.11%)
    6 / 319 (1.88%)
    7 / 475 (1.47%)
         occurrences all number
    8
    10
    6
    7
    Pneumonia
         subjects affected / exposed
    4 / 314 (1.27%)
    1 / 475 (0.21%)
    6 / 319 (1.88%)
    6 / 475 (1.26%)
         occurrences all number
    4
    1
    6
    6
    Urinary tract infection
         subjects affected / exposed
    4 / 314 (1.27%)
    5 / 475 (1.05%)
    8 / 319 (2.51%)
    3 / 475 (0.63%)
         occurrences all number
    4
    5
    8
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Mar 2016
    Protocol version 2.0: - Defined primary objective for Market Access and statistical analysis (Synopsis, Sections 4.1, 5.2, 5.5,5.7, 7.1.1) - Included reference for Bretaris® Genuair® and Bretaris® Genuair® Summary of Product Characteristics (SmPC) (Section 3, list of references) - Corrected doses for Atrovent and specified brand names for US and non-US countries (Synopsis, Sections 5.1, 5.4) - Replaced Visit 8 by follow-up phone call (Section 5.1, 5.3, 6.1) - Added clarification on procedures for the end of treatment (EOT) and end of study (EOS) visits, including 1h post-dose pulmonary function test (PFT) after COPD prescribed treatment (Section 5.1) - Added red blood cells morphology, white blood cells differential and mean corpuscular volume (MCV) in the laboratory assessments (Section 8.4.1)
    21 Mar 2016
    Protocol version 3.0: The collection of IP intake was included in the e-diary (Section 5.1)

    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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