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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel Group, Multi-Center Study to Assess the Efficacy and Safety of PT009 Compared to PT005, PT008, and Open-label Symbicort® Turbuhaler®, as an Active Control, on Lung Function over a 24-Week Treatment Period in Subjects With Moderate to Very Severe COPD

    Summary
    EudraCT number
    2016-000154-34
    Trial protocol
    CZ   HU   DE   PL  
    Global end of trial date
    30 Nov 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Mar 2019
    First version publication date
    21 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PT009002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02766608
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pearl Therapeutics, a Member of the AstraZeneca Group
    Sponsor organisation address
    200 Cardinal Way, Redwood City, United States, 94063
    Public contact
    Paul M. Dorinsky, MD, Pearl Therapeutics, a Member of the AstraZeneca Group, 1 6503052600, paul.dorinsky1@astrazeneca.com
    Scientific contact
    Paul M. Dorinsky, MD, Pearl Therapeutics, a Member of the AstraZeneca Group, 1 6503052600, paul.dorinsky1@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
    30 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the effects of BFF MDI relative to FF MDI and BD MDI on lung function
    Protection of trial subjects
    For subjects who were on ICS LABA, the ICS LABA was discontinued, however, then prescribed an ICS Monotherapy at an equivalent dosing regimen for the duration of the study. Subjects were also given sponsor provided Ventolin HFA as rescue medication.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 May 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
    Canada: 107
    Country: Number of subjects enrolled
    Czech Republic: 208
    Country: Number of subjects enrolled
    Germany: 135
    Country: Number of subjects enrolled
    Hungary: 201
    Country: Number of subjects enrolled
    Poland: 310
    Country: Number of subjects enrolled
    Russian Federation: 384
    Country: Number of subjects enrolled
    United States: 1016
    Worldwide total number of subjects
    2361
    EEA total number of subjects
    854
    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)
    1132
    From 65 to 84 years
    1229
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study randomized subjects at 244 study centers in 7 countries, from June 2016 and November 2017. The study period was scheduled to take up to approximately 30 weeks for each individual subject from the time of screening through the follow-up period.

    Pre-assignment
    Screening details
    Subjects were randomized in a 3:3:3:1:1 ratio to BFF 320/9.6, BFF 160/9.6, FF 9.6, BD 320, and Symbicort.

    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, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    Subjects assigned to blinded study drug will be instructed to dose while at home from the site-primed MDI only, unless all of the following replacement conditions are met: o Dose indicator is in the red zone (Refer to Appendix 1 for dose indicator reading instructions) o The dose indicator registers ≤ 10 puffs remaining, and o Their next scheduled study clinic visit is not the following day

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BFF MDI 320/9.6 μg
    Arm description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg
    Arm type
    Experimental

    Investigational medicinal product name
    Budesonide Formoterol Fumarate
    Investigational medicinal product code
    Other name
    BFF MDI
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 inhalations BID

    Arm title
    BFF MDI 160/9.6 μg
    Arm description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg
    Arm type
    Experimental

    Investigational medicinal product name
    Budesonide Formoterol Fumarate MDI
    Investigational medicinal product code
    Other name
    BFF MDI
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 inhalations BID

    Arm title
    FF MDI 9.6 μg
    Arm description
    Formoterol Fumarate Metered Dose Inhalation 9.6 μg
    Arm type
    Experimental

    Investigational medicinal product name
    Formoterol Fumarate MDI
    Investigational medicinal product code
    Other name
    FF MDI
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 inhalations BID

    Arm title
    BD MDI 320 μg
    Arm description
    Budesonide Metered Dose Inhalation 320 μg
    Arm type
    Experimental

    Investigational medicinal product name
    Budesonide MDI
    Investigational medicinal product code
    Other name
    BD MDI
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 inhalations

    Arm title
    Symbicort TBH 400/12 μg
    Arm description
    Symbicort Turbuhaler 400/12 μg
    Arm type
    Active control

    Investigational medicinal product name
    Symbicort Turbuhaler
    Investigational medicinal product code
    Other name
    Symbicort
    Pharmaceutical forms
    Pressurised inhalation, suspension
    Routes of administration
    Inhalation use
    Dosage and administration details
    Taken as 2 inhalations BID

    Number of subjects in period 1
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Started
    655
    637
    644
    206
    219
    Completed
    576
    567
    554
    169
    190
    Not completed
    79
    70
    90
    37
    29
         Protocol deviation
    -
    4
    4
    -
    1
         Physician decision
    3
    2
    3
    1
    2
         Administrative Reasons
    3
    1
    1
    -
    -
         Lack of efficacy
    16
    15
    32
    8
    2
         Protocol disc criteria
    3
    3
    4
    -
    -
         Adverse event, non-fatal
    27
    22
    17
    13
    12
         Consent withdrawn by subject
    21
    20
    24
    13
    10
         Lost to follow-up
    6
    3
    5
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BFF MDI 320/9.6 μg
    Reporting group description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

    Reporting group title
    BFF MDI 160/9.6 μg
    Reporting group description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

    Reporting group title
    FF MDI 9.6 μg
    Reporting group description
    Formoterol Fumarate Metered Dose Inhalation 9.6 μg

    Reporting group title
    BD MDI 320 μg
    Reporting group description
    Budesonide Metered Dose Inhalation 320 μg

    Reporting group title
    Symbicort TBH 400/12 μg
    Reporting group description
    Symbicort Turbuhaler 400/12 μg

    Reporting group values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg Total
    Number of subjects
    655 637 644 206 219 2361
    Age categorical
    mITT Population
    Units: Subjects
        Adults (18-64 years)
    322 298 313 101 98 1132
        From 65-84 years
    333 339 331 105 121 1229
    Age Continuous
    mITT Population
    Units: years
        least squares mean (standard deviation)
    64.2 ± 7.7 64.3 ± 7.6 64.1 ± 8.0 64.2 ± 7.4 65.3 ± 7.0 -
    Sex: Female, Male
    mITT Population
    Units: Subjects
        Female
    253 260 261 81 78 933
        Male
    402 377 383 125 141 1428
    Ethnicity (NIH/OMB)
    mITT Population
    Units: Subjects
        Hispanic or Latino
    16 18 21 8 6 69
        Not Hispanic or Latino
    637 616 623 198 212 2286
        Unknown or Not Reported
    2 3 0 0 1 6
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    2 2 2 0 0 6
        Asian
    1 1 0 0 1 3
        Native Hawaiian or Other Pacific Islander
    0 0 0 0 0 0
        Black or African American
    19 15 20 9 8 71
        White
    633 619 622 197 210 2281
        More than one race
    0 0 0 0 0 0
        Unknown or Not Reported
    0 0 0 0 0 0
    Subject analysis sets

    Subject analysis set title
    BFF MDI 320/9.6 μg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

    Subject analysis set title
    BFF MDI 160/9.6 μg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

    Subject analysis set title
    FF MDI 9.6 μg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Formoterol Fumarate Metered Dose Inhalation 9.6 μg

    Subject analysis set title
    BD MDI 320 μg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Budesonide Metered Dose Inhalation 320 μg

    Subject analysis set title
    Symbicort TBH 400/12 ug
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Symbicort Turbuhaler 400/12 ug

    Subject analysis sets values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 ug
    Number of subjects
    664
    649
    648
    209
    219
    Age categorical
    mITT Population
    Units: Subjects
        Adults (18-64 years)
    322
    298
    313
    101
    98
        From 65-84 years
    333
    339
    331
    105
    121
    Age Continuous
    mITT Population
    Units: years
        least squares mean (standard deviation)
    64.2 ± 7.7
    64.3 ± 7.6
    64.1 ± 8.0
    64.2 ± 7.4
    65.3 ± 7.0
    Sex: Female, Male
    mITT Population
    Units: Subjects
        Female
    253
    260
    261
    81
    78
        Male
    402
    377
    383
    125
    141
    Ethnicity (NIH/OMB)
    mITT Population
    Units: Subjects
        Hispanic or Latino
    16
    18
    21
    8
    6
        Not Hispanic or Latino
    637
    616
    623
    198
    212
        Unknown or Not Reported
    2
    3
    0
    0
    1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    2
    2
    2
    0
    0
        Asian
    1
    1
    0
    0
    1
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
    0
    0
        Black or African American
    19
    15
    20
    9
    8
        White
    633
    619
    622
    197
    210
        More than one race
    0
    0
    0
    0
    0
        Unknown or Not Reported
    0
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    BFF MDI 320/9.6 μg
    Reporting group description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

    Reporting group title
    BFF MDI 160/9.6 μg
    Reporting group description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

    Reporting group title
    FF MDI 9.6 μg
    Reporting group description
    Formoterol Fumarate Metered Dose Inhalation 9.6 μg

    Reporting group title
    BD MDI 320 μg
    Reporting group description
    Budesonide Metered Dose Inhalation 320 μg

    Reporting group title
    Symbicort TBH 400/12 μg
    Reporting group description
    Symbicort Turbuhaler 400/12 μg

    Subject analysis set title
    BFF MDI 320/9.6 μg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

    Subject analysis set title
    BFF MDI 160/9.6 μg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

    Subject analysis set title
    FF MDI 9.6 μg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Formoterol Fumarate Metered Dose Inhalation 9.6 μg

    Subject analysis set title
    BD MDI 320 μg
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Budesonide Metered Dose Inhalation 320 μg

    Subject analysis set title
    Symbicort TBH 400/12 ug
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Symbicort Turbuhaler 400/12 ug

    Primary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI versus FF MDI)

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    End point title
    Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI versus FF MDI)
    End point description
    Change from baseline in morning pre-dose trough FEV1 (Forced expiratory volume in 1 second) over 24 weeks (BFF MDI versus FF MDI)
    End point type
    Primary
    End point timeframe
    over 24 weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    627
    615
    613
    190
    211
    Units: Liter
        least squares mean (confidence interval 95%)
    0.058 (0.045 to 0.071)
    0.033 (0.020 to 0.047)
    0.027 (0.014 to 0.041)
    -0.029 (-0.053 to -0.004)
    0.067 (0.044 to 0.090)
    Statistical analysis title
    Baseline morning pre-dose FEV1 over 24 wks
    Statistical analysis description
    Primary endpoint analysis - BFF MDI versus FF MDI
    Comparison groups
    BFF MDI 320/9.6 μg v BFF MDI 160/9.6 μg v FF MDI 9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    2045
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    repeated measures linear mixed model
    Confidence interval
    Statistical analysis title
    Baseline morning pre-dose FEV1 over 24wks
    Statistical analysis description
    Primary endpoint BFF 320/9.6 vs Symbicort TBH 400/12 ug
    Comparison groups
    BFF MDI 320/9.6 μg v Symbicort TBH 400/12 μg
    Number of subjects included in analysis
    838
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    repeated measures linear mixed model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.036
         upper limit
    0.018
    Statistical analysis title
    Baseline morning pre-dose FEV1 over 24wks
    Statistical analysis description
    Primary endpoint BFF 160/9.6 vs Symbicort 400/12 ug
    Comparison groups
    BFF MDI 160/9.6 μg v Symbicort TBH 400/12 μg
    Number of subjects included in analysis
    826
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    repeated measures linear mixed model
    Parameter type
    LS Mean Difference
    Point estimate
    -0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.061
         upper limit
    -0.007

    Primary: Change from baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI)

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    End point title
    Change from baseline in FEV1 AUC0-4 (BFF MDI vs BD MDI)
    End point description
    Change from baseline in FEV1 (Forced Expiratory Volume) AUC0-4 (Area under the curve from 0 to 4 hours) (BFF MDI vs BD MDI)
    End point type
    Primary
    End point timeframe
    over 24 weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    654
    636
    643
    206
    218
    Units: Liter
        least squares mean (confidence interval 95%)
    0.211 (0.198 to 0.223)
    0.195 (0.183 to 0.208)
    0.188 (0.176 to 0.201)
    0.030 (0.008 to 0.052)
    0.202 (0.181 to 0.224)
    Statistical analysis title
    FEV1 AUC0-4
    Statistical analysis description
    Primary endpoint analysis Change from baseline in FEV1 AUC0-4: BFF vs BD
    Comparison groups
    BFF MDI 320/9.6 μg v BFF MDI 160/9.6 μg v FF MDI 9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    2139
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    repeated measures linear mixed model
    Confidence interval
    Statistical analysis title
    FEV1 AUC0-4
    Statistical analysis description
    Primary endpoint analysis -Change from baseline in FEV1 AUC0-4: BFF 320/9.6 ug vs Symbicort TBH 400/12 ug
    Comparison groups
    BFF MDI 320/9.6 μg v Symbicort TBH 400/12 μg
    Number of subjects included in analysis
    872
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    mixed model for repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.017
         upper limit
    0.033
    Statistical analysis title
    FEV1 AUC0-4
    Statistical analysis description
    Primary endpoint analysis Change from baseline in FEV1 AUC0-4: BFF 160/9.6 ug vs Symbicort TBH 400/12 ug
    Comparison groups
    BFF MDI 160/9.6 μg v Symbicort TBH 400/12 μg
    Number of subjects included in analysis
    854
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    LS Mean (SE)
    Point estimate
    -0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.032
         upper limit
    0.018
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.5769

    Secondary: Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI).

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    End point title
    Time to first moderate or severe COPD exacerbation (BFF MDI vs FF MDI).
    End point description
    Time to first moderate or severe COPD (Chronic Obstructive Pulmonary Disease) exacerbation (BFF MDI vs FF MDI).
    End point type
    Secondary
    End point timeframe
    over 24 Weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    111
    127
    150
    206
    219
    Units: Participants
    17
    20
    23
    19
    15
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in SGRQ over 24 weeks

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    End point title
    Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in SGRQ over 24 weeks
    End point description
    The SGRQ (St. George’s Respiratory Questionnaire) is a disease-specific questionnaire, self-completed by participants, used to evaluate the effect of BFF MDI, FF MDI, BD MDI, & Symbicort TBH on health-related quality of life as compared to placebo in subjects with COPD. The scores range from 0 (minimum, best possible health status) to 100 (maximum, worst possible health status). The SGRQ contains 76 items grouped into three domains (symptoms, activity and impacts). Change from Baseline at a particular visit was calculated as the SGRQ total score at that visit minus Baseline. A decrease from baseline in SGRQ total score of 4 units or more is considered a clinically meaningful improvement in quality of life.
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    649 [1]
    635 [2]
    640 [3]
    204 [4]
    217 [5]
    Units: Percentage of Subjects
        Percent observed
    47
    47
    44
    42
    48
    Notes
    [1] - Observed % (n/N) for Treatment 302 /649
    [2] - Observed % (n/N) for Treatment 299/635
    [3] - Observed % (n/N) for Treatment 279/640
    [4] - Observed % (n/N) for Treatment 86/204
    [5] - Observed % (n/N) for Treatment 105/217
    No statistical analyses for this end point

    Secondary: Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs BD MDI)

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    End point title
    Change from baseline in morning pre-dose trough FEV1 over 24 weeks (BFF MDI vs BD MDI)
    End point description
    Change from baseline in morning pre-dose trough FEV1(Forced Expiratory Volume in 1 second) over 24 weeks (BFF MDI vs BD MDI)
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    627
    615
    613
    190
    211
    Units: Liter
        least squares mean (confidence interval 95%)
    0.058 (0.045 to 0.071)
    0.033 (0.020 to 0.047)
    0.027 (0.014 to 0.041)
    -0.029 (-0.053 to -0.004)
    0.067 (0.044 to 0.090)
    No statistical analyses for this end point

    Secondary: Peak change from baseline in FEV1 over 24 weeks (BFF MDI vs BD MDI)

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    End point title
    Peak change from baseline in FEV1 over 24 weeks (BFF MDI vs BD MDI)
    End point description
    Peak change from baseline in FEV1 (Forced Expiratory Volume in 1 second) over 24 weeks (BFF MDI vs BD MDI)
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    654
    636
    643
    206
    218
    Units: Liter
        least squares mean (confidence interval 95%)
    0.289 (0.276 to 0.302)
    0.274 (0.261 to 0.287)
    0.269 (0.256 to 0.282)
    0.120 (0.097 to 0.143)
    0.281 (0.259 to 0.304)
    No statistical analyses for this end point

    Secondary: Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)

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    End point title
    Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)
    End point description
    Change from baseline in average daily rescue Ventolin HFA use over 24 weeks (BFF MDI vs BD MDI)
    End point type
    Secondary
    End point timeframe
    over 24 Weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    654
    636
    641
    206
    218
    Units: Puffs per day
        least squares mean (confidence interval 95%)
    -1.3 (-1.5 to -1.1)
    -1.3 (-1.4 to -1.1)
    -1.1 (-1.2 to -0.9)
    -0.6 (-0.9 to -0.3)
    -1.2 (-1.5 to -0.9)
    No statistical analyses for this end point

    Secondary: Time to onset of action on Day 1 - 5 Minutes (BFF MDI vs BD MDI)

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    End point title
    Time to onset of action on Day 1 - 5 Minutes (BFF MDI vs BD MDI)
    End point description
    Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 5 Minutes.
    End point type
    Secondary
    End point timeframe
    Day 1 - 5 Minutes
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    535
    536
    534
    171
    173
    Units: Liter
        least squares mean (confidence interval 95%)
    0.157 (0.148 to 0.166)
    0.151 (0.142 to 0.161)
    0.160 (0.150 to 0.169)
    0.025 (0.009 to 0.041)
    0.131 (0.115 to 0.148)
    No statistical analyses for this end point

    Secondary: Time to onset of action on Day 1 - 15 Minutes (BFF MDI vs BD MDI)

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    End point title
    Time to onset of action on Day 1 - 15 Minutes (BFF MDI vs BD MDI)
    End point description
    Time to onset of action on Day 1- 15 Minutes (BFF MDI vs BD MDI). Change from baseline at 15 Minutes.
    End point type
    Secondary
    End point timeframe
    Day 1 - 15 Minutes
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    624
    615
    612
    203
    211
    Units: Liter
        least squares mean (confidence interval 95%)
    0.190 (0.180 to 0.200)
    0.186 (0.176 to 0.196)
    0.201 (0.191 to 0.211)
    0.040 (0.022 to 0.058)
    0.167 (0.149 to 0.184)
    No statistical analyses for this end point

    Secondary: Time to onset of action on Day 1 - 30 Minutes (BFF MDI vs BD MDI)

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    End point title
    Time to onset of action on Day 1 - 30 Minutes (BFF MDI vs BD MDI)
    End point description
    Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 30 Minutes.
    End point type
    Secondary
    End point timeframe
    Day 1 - 30 Minutes
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    648
    627
    638
    203
    214
    Units: Liter
        least squares mean (confidence interval 95%)
    0.207 (0.196 to 0.217)
    0.207 (0.196 to 0.218)
    0.215 (0.205 to 0.226)
    0.047 (0.028 to 0.066)
    0.190 (0.172 to 0.209)
    No statistical analyses for this end point

    Secondary: Time to onset of action on Day 1 - 1 Hour (BFF MDI vs BD MDI)

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    End point title
    Time to onset of action on Day 1 - 1 Hour (BFF MDI vs BD MDI)
    End point description
    Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 1 hour.
    End point type
    Secondary
    End point timeframe
    Day 1 - 1 Hour
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    649
    628
    640
    204
    215
    Units: Liter
        least squares mean (confidence interval 95%)
    0.225 (0.213 to 0.236)
    0.221 (0.210 to 0.233)
    0.236 (0.225 to 0.248)
    0.053 (0.033 to 0.073)
    0.211 (0.191 to 0.231)
    No statistical analyses for this end point

    Secondary: Time to onset of action on Day 1 - 2 Hours (BFF MDI vs BD MDI)

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    End point title
    Time to onset of action on Day 1 - 2 Hours (BFF MDI vs BD MDI)
    End point description
    Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 2 hours.
    End point type
    Secondary
    End point timeframe
    Day 1 - 2 Hours
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    649
    629
    636
    205
    217
    Units: Liter
        least squares mean (confidence interval 95%)
    0.253 (0.241 to 0.265)
    0.234 (0.222 to 0.247)
    0.244 (0.231 to 0.256)
    0.063 (0.042 to 0.085)
    0.221 (0.200 to 0.243)
    No statistical analyses for this end point

    Secondary: Time to onset of action on Day 1 - 4 Hours (BFF MDI vs BD MDI)

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    End point title
    Time to onset of action on Day 1 - 4 Hours (BFF MDI vs BD MDI)
    End point description
    Time to onset of action on Day 1 (BFF MDI vs BD MDI). Change from baseline at 4 hours.
    End point type
    Secondary
    End point timeframe
    Day 1 - 4 Hours
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    651
    630
    634
    201
    217
    Units: Time Point
        least squares mean (confidence interval 95%)
    0.230 (0.216 to 0.243)
    0.215 (0.202 to 0.229)
    0.212 (0.199 to 0.226)
    0.073 (0.049 to 0.097)
    0.209 (0.186 to 0.232)
    No statistical analyses for this end point

    Secondary: Time to CID (BFF MDI vs FF MDI)

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    End point title
    Time to CID (BFF MDI vs FF MDI)
    End point description
    Time to Clinically Important deterioration (BFF MDI vs FF MDI).
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    111 [6]
    127 [7]
    150 [8]
    39 [9]
    32 [10]
    Units: Participants
        number (not applicable)
    17
    20
    23
    19
    15
    Notes
    [6] - % of subjects that had at least one COPD Exacerbation
    [7] - % of subjects that had at least one COPD Exacerbation
    [8] - % of subjects that had at least one COPD Exacerbation
    [9] - % of subjects that had at least one COPD Exacerbation
    [10] - % of subjects that had at least one COPD Exacerbation
    No statistical analyses for this end point

    Secondary: TDI focal score over 24 weeks

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    End point title
    TDI focal score over 24 weeks
    End point description
    TDI focal score over 24 weeks (BFF MDI vs FF MDI; BFF MDI vs BD MDI; BFF MDI 320/9.6 μg vs Symbicort TBH, non-inferiority).
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    618
    607
    605
    185
    206
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    1.12 (0.98 to 1.27)
    1.20 (1.06 to 1.35)
    0.98 (0.83 to 1.12)
    0.59 (0.33 to 0.86)
    1.07 (0.81 to 1.32)
    No statistical analyses for this end point

    Secondary: Change from baseline in the E-RS-Total Score over 24 weeks

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    End point title
    Change from baseline in the E-RS-Total Score over 24 weeks
    End point description
    Change from baseline in the E-RS Total Score over 24 weeks (BFF MDI vs FF MDI; BFF MDI vs BD MDI; BFF MDI 320/9.6 μg vs Symbicort TBH, noninferiority)
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Number of subjects analysed
    655
    637
    641
    206
    218
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    -1.5 (-1.8 to -1.2)
    -1.7 (-2.0 to -1.4)
    -1.3 (-1.6 to -1.0)
    -0.9 (-1.4 to -0.3)
    -1.4 (-1.9 to -0.9)
    No statistical analyses for this end point

    Other pre-specified: Substudy: 12-hour PFT endpoint FEV1 AUC0-12

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    End point title
    Substudy: 12-hour PFT endpoint FEV1 AUC0-12 [11]
    End point description
    Substudy: 12-hour PFT (Pulmonary Function Test) endpoint FEV1 (Forced Expiratory Volume) AUC0-12 (Area under the Curve 0-12)
    End point type
    Other pre-specified
    End point timeframe
    at Week 12
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The subjects on Symbicort TBH 400ug Arm, did not participate in the Sub-Study
    End point values
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg
    Number of subjects analysed
    160
    167
    162
    47
    Units: Liter
        least squares mean (confidence interval 95%)
    0.135 (0.107 to 0.163)
    0.124 (0.097 to 0.152)
    0.117 (0.089 to 0.145)
    0.024 (-0.028 to 0.075)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time the subject signed informed consent throughout the treatment period and up to 14 days following the last dose of study drug
    Adverse event reporting additional description
    Serious Adverse Events were collected from the time the subject signed informed consent throughout the treatment period and up to approximately 30 weeks, which includes screening and follow up (14 days after last dose of study drug). 
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    BFF MDI 320/9.6 μg
    Reporting group description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 320/9.6 μg

    Reporting group title
    BFF MDI 160/9.6 μg
    Reporting group description
    Budesonide Formoterol Fumarate Metered Dose Inhalation 160/9.6 μg

    Reporting group title
    FF MDI 9.6 μg
    Reporting group description
    Formoterol Fumarate Metered Dose Inhalation 9.6 μg

    Reporting group title
    BD MDI 320 μg
    Reporting group description
    Budesonide Metered Dose Inhalation 320 μg

    Reporting group title
    Symbicort TBH 400/12 μg
    Reporting group description
    Symbicort Turbuhaler 400/12 μg

    Serious adverse events
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 655 (6.41%)
    45 / 637 (7.06%)
    72 / 644 (11.18%)
    15 / 206 (7.28%)
    20 / 219 (9.13%)
         number of deaths (all causes)
    3
    2
    2
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Haematoma
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Hypertensive emergency
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Peripheral ischaemia
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Brain cancer metastatic
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Breast cancer male
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Bronchial carcinoma
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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 neoplasm
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Mesothelioma
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Metastases to liver
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Metastatic carcinoma of the bladder
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Prostate cancer
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Chest pain
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Death
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Incarcerated hernia
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Sudden cardiac death
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Reproductive system and breast disorders
    Prostatic haemorrhage
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Dural tear
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Femur fracture
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Forearm fracture
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Lower limb fracture
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Radius fracture
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Rib fracture
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Thermal burn
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Upper limb fracture
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Skull fractured base
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 655 (0.15%)
    5 / 637 (0.78%)
    2 / 644 (0.31%)
    1 / 206 (0.49%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 637 (0.16%)
    1 / 644 (0.16%)
    2 / 206 (0.97%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 2
    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 / 655 (0.00%)
    2 / 637 (0.31%)
    2 / 644 (0.31%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 655 (0.15%)
    2 / 637 (0.31%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 637 (0.31%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    1 / 206 (0.49%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 655 (0.31%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 655 (0.00%)
    2 / 637 (0.31%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    1 / 206 (0.49%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Cardiac arrest
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Coronary artery stenosis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    15 / 655 (2.29%)
    10 / 637 (1.57%)
    29 / 644 (4.50%)
    2 / 206 (0.97%)
    6 / 219 (2.74%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 10
    0 / 35
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 655 (0.31%)
    2 / 637 (0.31%)
    4 / 644 (0.62%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    2 / 644 (0.31%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Carotid artery stenosis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Embolic stroke
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Epilepsy
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Hypoaesthesia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Intracranial aneurysm
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Syncope
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Cataract
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    2 / 644 (0.31%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Colitis ischaemic
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Diverticulum intestinal
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Gastrointestinal ulcer
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Hiatus hernia
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Inflammatory bowel disease
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Pancreatitis
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Strangulated umbilical hernia
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    1 / 206 (0.49%)
    0 / 219 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    1 / 206 (0.49%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    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 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Chronic kidney disease
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Hypertonic bladder
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Renal tubular necrosis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Renal cyst
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Product issues
    Device battery issue
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Arthritis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Bursitis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Tendonitis
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Diabetes mellitus
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Diabetes with hyperosmolarity
         subjects affected / exposed
    1 / 655 (0.15%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Electrolyte imbalance
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Gout
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Pneumonia
         subjects affected / exposed
    4 / 655 (0.61%)
    5 / 637 (0.78%)
    6 / 644 (0.93%)
    0 / 206 (0.00%)
    3 / 219 (1.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 7
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia gangrenous
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Breast abscess
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Cellulitis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    1 / 644 (0.16%)
    0 / 206 (0.00%)
    0 / 219 (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
    Sepsis
         subjects affected / exposed
    0 / 655 (0.00%)
    0 / 637 (0.00%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    1 / 219 (0.46%)
         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
    Staphylococcal infection
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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
    Tooth abscess
         subjects affected / exposed
    0 / 655 (0.00%)
    1 / 637 (0.16%)
    0 / 644 (0.00%)
    0 / 206 (0.00%)
    0 / 219 (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: 2%
    Non-serious adverse events
    BFF MDI 320/9.6 μg BFF MDI 160/9.6 μg FF MDI 9.6 μg BD MDI 320 μg Symbicort TBH 400/12 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    240 / 655 (36.64%)
    201 / 637 (31.55%)
    219 / 644 (34.01%)
    75 / 206 (36.41%)
    57 / 219 (26.03%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 655 (2.14%)
    22 / 637 (3.45%)
    15 / 644 (2.33%)
    5 / 206 (2.43%)
    4 / 219 (1.83%)
         occurrences all number
    14
    22
    15
    5
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 655 (1.07%)
    15 / 637 (2.35%)
    15 / 644 (2.33%)
    7 / 206 (3.40%)
    0 / 219 (0.00%)
         occurrences all number
    8
    15
    15
    7
    0
    Dyspnoea
         subjects affected / exposed
    12 / 655 (1.83%)
    11 / 637 (1.73%)
    9 / 644 (1.40%)
    7 / 206 (3.40%)
    3 / 219 (1.37%)
         occurrences all number
    12
    11
    9
    7
    3
    Dysphonia
         subjects affected / exposed
    16 / 655 (2.44%)
    13 / 637 (2.04%)
    3 / 644 (0.47%)
    2 / 206 (0.97%)
    1 / 219 (0.46%)
         occurrences all number
    16
    13
    3
    2
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 655 (2.90%)
    8 / 637 (1.26%)
    15 / 644 (2.33%)
    3 / 206 (1.46%)
    1 / 219 (0.46%)
         occurrences all number
    27
    10
    15
    4
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 655 (0.15%)
    1 / 637 (0.16%)
    5 / 644 (0.78%)
    5 / 206 (2.43%)
    1 / 219 (0.46%)
         occurrences all number
    1
    1
    5
    5
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 655 (0.92%)
    2 / 637 (0.31%)
    4 / 644 (0.62%)
    5 / 206 (2.43%)
    1 / 219 (0.46%)
         occurrences all number
    6
    2
    4
    5
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 655 (1.37%)
    9 / 637 (1.41%)
    9 / 644 (1.40%)
    5 / 206 (2.43%)
    3 / 219 (1.37%)
         occurrences all number
    9
    9
    9
    6
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    18 / 655 (2.75%)
    13 / 637 (2.04%)
    18 / 644 (2.80%)
    3 / 206 (1.46%)
    2 / 219 (0.91%)
         occurrences all number
    21
    14
    19
    3
    2
    Muscle spasms
         subjects affected / exposed
    14 / 655 (2.14%)
    6 / 637 (0.94%)
    6 / 644 (0.93%)
    0 / 206 (0.00%)
    8 / 219 (3.65%)
         occurrences all number
    15
    6
    7
    0
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    40 / 655 (6.11%)
    40 / 637 (6.28%)
    43 / 644 (6.68%)
    17 / 206 (8.25%)
    14 / 219 (6.39%)
         occurrences all number
    46
    44
    46
    18
    18
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 655 (3.82%)
    21 / 637 (3.30%)
    20 / 644 (3.11%)
    5 / 206 (2.43%)
    3 / 219 (1.37%)
         occurrences all number
    27
    24
    20
    7
    3
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    16 / 655 (2.44%)
    10 / 637 (1.57%)
    30 / 644 (4.66%)
    2 / 206 (0.97%)
    6 / 219 (2.74%)
         occurrences all number
    17
    10
    36
    2
    6
    Oral candidiasis
         subjects affected / exposed
    17 / 655 (2.60%)
    14 / 637 (2.20%)
    5 / 644 (0.78%)
    3 / 206 (1.46%)
    3 / 219 (1.37%)
         occurrences all number
    18
    15
    6
    3
    3
    Bronchitis
         subjects affected / exposed
    16 / 655 (2.44%)
    7 / 637 (1.10%)
    10 / 644 (1.55%)
    4 / 206 (1.94%)
    2 / 219 (0.91%)
         occurrences all number
    17
    8
    10
    4
    2
    Sinusitis
         subjects affected / exposed
    10 / 655 (1.53%)
    9 / 637 (1.41%)
    12 / 644 (1.86%)
    2 / 206 (0.97%)
    5 / 219 (2.28%)
         occurrences all number
    12
    10
    13
    2
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2016
    Clarified dose of open label Symbicort® TBH Updated synopsis, Safety endpoints, Inclusion/Exclusion Criteria.
    24 Oct 2017
    Updated Protocol objective, updated endpoints, clarification of statistical methods.

    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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