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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 on COPD Exacerbations over a variable-length (12-52 week) Treatment Period in Subjects With Moderate to Very Severe COPD

    Summary
    EudraCT number
    		 2016-000155-28
    Trial protocol
    		 DK   BE   GB   DE   ES   AT   IT  
    Global end of trial date
    04 Apr 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    PT009003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02727660
    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
    04 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the effects of BFF MDI relative to FF MDI on lung function.
    Protection of trial subjects
    Subjects who are receiving an ICS/LABA will discontinue the ICS/LABA, but continue the ICS component for the remainder of the Screening Period. Subjects treated with an ICS as part of their inhaled maintenance therapy will continue their ICS for the remainder of the Screening Period. Sponsor-provided Ventolin HFA to be administered as needed, up to 8 inhalations per day, for control of COPD symptoms. Subjects receiving phosphodiesterase inhibitors (e.g., roflumilast) at stable doses for at least 4 weeks prior to Visit 1, may continue on these medications throughout the Screening and Randomized Treatment periods.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Apr 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
    Argentina: 182
    Country: Number of subjects enrolled
    Austria: 22
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Brazil: 62
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Chile: 41
    Country: Number of subjects enrolled
    Germany: 49
    Country: Number of subjects enrolled
    Denmark: 65
    Country: Number of subjects enrolled
    Spain: 61
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    Italy: 37
    Country: Number of subjects enrolled
    Mexico: 74
    Country: Number of subjects enrolled
    Norway: 29
    Country: Number of subjects enrolled
    Peru: 132
    Country: Number of subjects enrolled
    Russian Federation: 123
    Country: Number of subjects enrolled
    Sweden: 23
    Country: Number of subjects enrolled
    United States: 761
    Country: Number of subjects enrolled
    South Africa: 100
    Worldwide total number of subjects
    1843
    EEA total number of subjects
    334
    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)
    844
    From 65 to 84 years
    999
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study screened subjects at 292 study centers in 18 countries and randomized subjects at 259 study centers, from May 2016 to April 2018.

    Pre-assignment
    Screening details
    		 Subjects were randomized in a 1:1:1 ratio to BFF MDI 320/9.6 μg, BFF MDI 160/9.6 μg, and FF MDI 9.6 μg treatment groups

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BFF MDI 320/9.6 ug
    Arm description
    		 Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide Formoterol Fumarate MDI
    Investigational medicinal product code
    Other name
    BFF MDI 160/4.8 ug
    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 ug
    Arm description
    		 Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide Formoterol Fumarate MDI
    Investigational medicinal product code
    Other name
    BFF MDI 80/4.8 ug
    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 ug
    Arm description
    		 Formoterol Fumarate Metered dose inhalation 9.6 ug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Formoterol Fumarate MDI
    Investigational medicinal product code
    Other name
    FF MDI 4.8 ug
    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 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug
    Started
    619
    617
    607
    Completed
    503
    501
    442
    Not completed
    116
    116
    165
         Administrative Reasons
    2
    3
    4
         Consent withdrawn by subject
    26
    25
    30
         Physician decision
    3
    8
    14
         Adverse event, non-fatal
    28
    21
    32
         Protocol Specified Disc. Criteria
    5
    5
    2
         Lost to follow-up
    5
    9
    8
         Lack of efficacy
    40
    40
    70
         Protocol deviation
    7
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BFF MDI 320/9.6 ug
    Reporting group description
    		 Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug

    Reporting group title
    BFF MDI 160/9.6 ug
    Reporting group description
    		 Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug

    Reporting group title
    FF MDI 9.6 ug
    Reporting group description
    		 Formoterol Fumarate Metered dose inhalation 9.6 ug

    Reporting group values
    		 BFF MDI 320/9.6 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug Total
    Number of subjects
    		 619 617 607 1843
    Age categorical
    mITT Population
    Units: Subjects
        Adults (18-64 years)
    		 272 299 273 844
        From 65-84 years
    		 347 318 334 999
    Age Continuous
    mITT Population
    Units: years
        arithmetic mean (standard deviation)
    		 65.3 ± 8.1 64.5 ± 8.4 64.8 ± 8.5 -
    Sex: Female, Male
    mITT Population
    Units: Subjects
        Female
    		 252 272 268 792
        Male
    		 367 345 339 1051
    Race (NIH/OMB)
    mITT Population
    Units: Subjects
        American Indian or Alaska Native
    		 26 18 24 68
        Asian
    		 1 7 4 12
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        Black or African American
    		 30 22 29 81
        White
    		 514 516 504 1534
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 47 54 46 147
    Ethnicity (NIH/OMB)
    mITT Population
    Units: Subjects
        Hispanic or Latino
    		 190 200 190 580
        Not Hispanic or Latino
    		 423 414 412 1249
        Unknown or Not Reported
    		 6 3 5 14
    Subject analysis sets

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Intent-To-Treat (mITT) Population is defined as all subjects who were randomized to treatment, received any amount of the study treatment, and had post-randomization data obtained prior to discontinuation from treatment.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population is defined as all subjects who were randomized to treatment and received at least one dose of the study treatment. Subjects are analyzed according to treatment received rather than randomized.

    Subject analysis sets values
    		 mITT Safety Population
    Number of subjects
    1843
    1843
    Age categorical
    mITT Population
    Units: Subjects
        Adults (18-64 years)
    844
    844
        From 65-84 years
    999
    999
    Age Continuous
    mITT Population
    Units: years
        arithmetic mean (standard deviation)
    64.9 ± 8.3
    64.9 ± 8.3
    Sex: Female, Male
    mITT Population
    Units: Subjects
        Female
    792
    792
        Male
    1051
    1051
    Race (NIH/OMB)
    mITT Population
    Units: Subjects
        American Indian or Alaska Native
    68
    68
        Asian
    12
    12
        Native Hawaiian or Other Pacific Islander
    1
    1
        Black or African American
    81
    81
        White
    1534
    1534
        More than one race
    0
    0
        Unknown or Not Reported
    147
    147
    Ethnicity (NIH/OMB)
    mITT Population
    Units: Subjects
        Hispanic or Latino
    580
    580
        Not Hispanic or Latino
    1249
    1249
        Unknown or Not Reported
    14
    14

    End points

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    End points reporting groups
    Reporting group title
    BFF MDI 320/9.6 ug
    Reporting group description
    		 Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug

    Reporting group title
    BFF MDI 160/9.6 ug
    Reporting group description
    		 Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug

    Reporting group title
    FF MDI 9.6 ug
    Reporting group description
    		 Formoterol Fumarate Metered dose inhalation 9.6 ug

    Subject analysis set title
    mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    The Modified Intent-To-Treat (mITT) Population is defined as all subjects who were randomized to treatment, received any amount of the study treatment, and had post-randomization data obtained prior to discontinuation from treatment.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Population is defined as all subjects who were randomized to treatment and received at least one dose of the study treatment. Subjects are analyzed according to treatment received rather than randomized.

    Primary: Morning pre-dose trough FEV1

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    End point title
    		 Morning pre-dose trough FEV1
    End point description
    Morning pre-dose trough FEV1 (Forced Expiratory Volume in one second) over 24 weeks
    End point type
    Primary
    End point timeframe
    over 24 weeks
    End point values
    		 BFF MDI 320/9.6 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug
    Number of subjects analysed
    578
    590
    559
    Units: Liter
        least squares mean (confidence interval 95%)
    0.063 (0.047 to 0.079)
    0.059 (0.044 to 0.074)
    0.024 (0.009 to 0.040)
    Statistical analysis title
    		 Morning pre-dose trough FEV1
    Statistical analysis description
    Primary endpoint analysis - BFF MDI versus FF MDI
    Comparison groups
    BFF MDI 320/9.6 ug v FF MDI 9.6 ug
    Number of subjects included in analysis
    1137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 repeated measures linear mixed model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.039
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.018
         upper limit
    		 0.059
    Statistical analysis title
    		 Morning pre-dose trough FEV1
    Statistical analysis description
    Primary endpoint analysis - BFF MDI versus FF MDI
    Comparison groups
    BFF MDI 160/9.6 ug v FF MDI 9.6 ug
    Number of subjects included in analysis
    1149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≥ 0.05
    Method
    		 repeated measures linear mixed model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.05
    Confidence interval
         level
    		 0.03%
         sides
    2-sided
         lower limit
    		 0.014
         upper limit
    		 0.055

    Secondary: Time to first moderate or severe COPD exacerbation

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    End point title
    		 Time to first moderate or severe COPD exacerbation
    End point description
    Time to first moderate or severe COPD (Chronic Obstructive Pulmonary Disease) exacerbation over 52 weeks
    End point type
    Secondary
    End point timeframe
    over 52 weeks
    End point values
    		 BFF MDI 320/9.6 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug
    Number of subjects analysed
    619
    617
    607
    Units: Participants
        No of subj with ≥1 events
    220
    223
    241
    No statistical analyses for this end point

    Secondary: Time to first clinically important deterioration in COPD

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    End point title
    		 Time to first clinically important deterioration in COPD
    End point description
    Time to first clinically important deterioration in COPD over 52 weeks
    End point type
    Secondary
    End point timeframe
    over 52 weeks
    End point values
    		 BFF MDI 320/9.6 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug
    Number of subjects analysed
    619
    617
    607
    Units: Number
    469
    462
    491
    No statistical analyses for this end point

    Secondary: Change from baseline in average daily rescue Ventolin HFA use

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    End point title
    		 Change from baseline in average daily rescue Ventolin HFA use
    End point description
    Change from baseline in average daily rescue Ventolin HFA use over 24 weeks
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    		 BFF MDI 320/9.6 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug
    Number of subjects analysed
    612
    610
    599
    Units: Puffs per day
        least squares mean (confidence interval 95%)
    -1.0 (-1.2 to -0.8)
    -1.0 (-1.1 to -0.8)
    -0.6 (-0.8 to -0.4)
    No statistical analyses for this end point

    Secondary: Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in Saint George’s Respiratory Questionnaire (SGRQ) total score

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    End point title
    		 Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in Saint George’s Respiratory Questionnaire (SGRQ) total score
    End point description
    Percentage of subjects achieving an MCID (Minimal clinically important difference) of 4 units or more in Saint George’s Respiratory Questionnaire (SGRQ) total score over 24 weeks
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    		 BFF MDI 320/9.6 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug
    Number of subjects analysed
    606 [1]
    613 [2]
    596 [3]
    Units: scores on a scale
        Percent observed
    53
    53
    43
    Notes
    [1] - Observed % (n/N) for Treatment 320/606
    [2] - Observed % (n/N) for Treatment 326/613
    [3] - Observed % (n/N) for Treatment 254/596
    No statistical analyses for this end point

    Secondary: Change from baseline in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) total score over the treatment period

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    End point title
    		 Change from baseline in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) total score over the treatment period
    End point description
    Change from baseline in the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) total score over the treatment period over 52 weeks
    End point type
    Secondary
    End point timeframe
    over 52 weeks
    End point values
    		 BFF MDI 320/9.6 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug
    Number of subjects analysed
    614
    613
    597
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    -2.4 (-3.2 to -1.6)
    -2.5 (-3.3 to -1.7)
    -1.0 (-1.8 to -0.2)
    No statistical analyses for this end point

    Secondary: Transient Dyspnea Index (TDI) focal score

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    End point title
    		 Transient Dyspnea Index (TDI) focal score
    End point description
    Transient Dyspnea Index (TDI) focal score over 24 weeks
    End point type
    Secondary
    End point timeframe
    over 24 weeks
    End point values
    		 BFF MDI 320/9.6 ug BFF MDI 160/9.6 ug FF MDI 9.6 ug
    Number of subjects analysed
    566
    578
    550
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    1.32 (1.10 to 1.53)
    1.30 (1.09 to 1.51)
    1.06 (0.85 to 1.28)
    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 52 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
    21.0
    Reporting groups
    Reporting group title
    BFF MDI 320/9.6 ug
    Reporting group description
    		 Budesonide Formoterol Fumarate Metered dose inhalation 320/9.6 ug

    Reporting group title
    FF MDI 9.6 ug
    Reporting group description
    		 Formoterol Fumarate Metered dose inhalation 9.6 ug

    Reporting group title
    BFF MDI 160/9.6 ug
    Reporting group description
    		 Budesonide Formoterol Fumarate Metered dose inhalation 160/9.6 ug

    Serious adverse events
    		 BFF MDI 320/9.6 ug FF MDI 9.6 ug BFF MDI 160/9.6 ug
    Total subjects affected by serious adverse events
         subjects affected / exposed
    60 / 619 (9.69%)
    83 / 607 (13.67%)
    78 / 617 (12.64%)
         number of deaths (all causes)
    3
    8
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 619 (0.32%)
    1 / 607 (0.16%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma stage III
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic Cancer
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma stage III
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 619 (0.16%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disease
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 619 (0.32%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    27 / 619 (4.36%)
    50 / 607 (8.24%)
    30 / 617 (4.86%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 65
    0 / 33
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 619 (0.32%)
    6 / 607 (0.99%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 619 (0.16%)
    1 / 607 (0.16%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status change
         subjects affected / exposed
    1 / 619 (0.16%)
    1 / 607 (0.16%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal injury
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fascial rupture
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 619 (0.00%)
    4 / 607 (0.66%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 619 (0.16%)
    1 / 607 (0.16%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrilation
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    3 / 617 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 619 (0.00%)
    2 / 607 (0.33%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonae
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 619 (0.16%)
    2 / 607 (0.33%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 619 (0.00%)
    2 / 607 (0.33%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    3 / 617 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 619 (0.16%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 619 (0.00%)
    2 / 607 (0.33%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal tubular acidosis
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 619 (0.97%)
    9 / 607 (1.48%)
    12 / 617 (1.94%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 619 (0.16%)
    1 / 607 (0.16%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 619 (0.16%)
    2 / 607 (0.33%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    2 / 617 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 619 (0.16%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess intestinal
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocele male infected
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pnuemonia mycoplasmal
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 619 (0.00%)
    0 / 607 (0.00%)
    1 / 617 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 619 (0.16%)
    0 / 607 (0.00%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovalaemia
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type II diabetes mellitus
         subjects affected / exposed
    0 / 619 (0.00%)
    1 / 607 (0.16%)
    0 / 617 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 BFF MDI 320/9.6 ug FF MDI 9.6 ug BFF MDI 160/9.6 ug
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    266 / 619 (42.97%)
    268 / 607 (44.15%)
    279 / 617 (45.22%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    15 / 619 (2.42%)
    14 / 607 (2.31%)
    15 / 617 (2.43%)
         occurrences all number
    15
    14
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 619 (2.58%)
    18 / 607 (2.97%)
    19 / 617 (3.08%)
         occurrences all number
    24
    20
    24
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 619 (2.10%)
    10 / 607 (1.65%)
    10 / 617 (1.62%)
         occurrences all number
    14
    11
    11
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    27 / 619 (4.36%)
    50 / 607 (8.24%)
    30 / 617 (4.86%)
         occurrences all number
    32
    65
    33
    Dyspnoea
         subjects affected / exposed
    23 / 619 (3.72%)
    16 / 607 (2.64%)
    16 / 617 (2.59%)
         occurrences all number
    23
    18
    19
    Cough
         subjects affected / exposed
    14 / 619 (2.26%)
    9 / 607 (1.48%)
    15 / 617 (2.43%)
         occurrences all number
    15
    9
    17
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 619 (2.42%)
    11 / 607 (1.81%)
    17 / 617 (2.76%)
         occurrences all number
    21
    13
    17
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    41 / 619 (6.62%)
    36 / 607 (5.93%)
    53 / 617 (8.59%)
         occurrences all number
    53
    43
    61
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 619 (4.52%)
    24 / 607 (3.95%)
    14 / 617 (2.27%)
         occurrences all number
    29
    28
    18
    Pneumonia
         subjects affected / exposed
    14 / 619 (2.26%)
    15 / 607 (2.47%)
    19 / 617 (3.08%)
         occurrences all number
    14
    15
    20
    Influenza
         subjects affected / exposed
    15 / 619 (2.42%)
    10 / 607 (1.65%)
    19 / 617 (3.08%)
         occurrences all number
    15
    10
    20
    Bronchitis
         subjects affected / exposed
    11 / 619 (1.78%)
    10 / 607 (1.65%)
    13 / 617 (2.11%)
         occurrences all number
    11
    14
    15
    Sinusitis
         subjects affected / exposed
    9 / 619 (1.45%)
    13 / 607 (2.14%)
    9 / 617 (1.46%)
         occurrences all number
    9
    13
    11
    Acute sinusitis
         subjects affected / exposed
    2 / 619 (0.32%)
    12 / 607 (1.98%)
    6 / 617 (0.97%)
         occurrences all number
    2
    17
    10
    Oral candidiasis
         subjects affected / exposed
    13 / 619 (2.10%)
    7 / 607 (1.15%)
    6 / 617 (0.97%)
         occurrences all number
    16
    8
    7
    Urinary tract infection
         subjects affected / exposed
    10 / 619 (1.62%)
    13 / 607 (2.14%)
    18 / 617 (2.92%)
         occurrences all number
    12
    15
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2016
    Sponsor contact information updated, Clarification to study population, updated inclusion/exclusion criteria, con meds, allowed meds, prohibited meds, and visit schedule.
    15 Dec 2016
    Updated study objectives, study design and plan, study duration, exacerbation history, and procedures.
    08 Jan 2018
    Clarified synopsis, HCRU endpoints, smoking status, estimands, mITT population. Updated statistical model definition of CID across PT010 & PT009 programs.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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