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    Clinical Trial Results:
    A placebo and active controlled study to assess the longterm safety of once daily QVA149 for 52 weeks in chronic obstructive pulmonary disease (COPD) patients with moderate to severe airflow limitation Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2012-002057-38
    Trial protocol
    		 SI   HU   GB   LV   EE   PL  
    Global end of trial date
    05 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2018
    First version publication date
    12 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CQVA149A2339
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01610037
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    05 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of QVA149 110/50 μg o.d. compared to placebo in terms of overall (serious adverse event) SAE rate from initiation of study treatment through 30 days post last treatment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Oct 2012
    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
    Colombia: 23
    Country: Number of subjects enrolled
    Croatia: 45
    Country: Number of subjects enrolled
    Estonia: 45
    Country: Number of subjects enrolled
    United Kingdom: 70
    Country: Number of subjects enrolled
    Hungary: 137
    Country: Number of subjects enrolled
    India: 88
    Country: Number of subjects enrolled
    Israel: 83
    Country: Number of subjects enrolled
    Korea, Republic of: 105
    Country: Number of subjects enrolled
    Latvia: 34
    Country: Number of subjects enrolled
    Mexico: 18
    Country: Number of subjects enrolled
    Panama: 23
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Russian Federation: 114
    Country: Number of subjects enrolled
    Serbia: 38
    Country: Number of subjects enrolled
    Slovenia: 38
    Country: Number of subjects enrolled
    Turkey: 52
    Country: Number of subjects enrolled
    Argentina: 249
    Worldwide total number of subjects
    1216
    EEA total number of subjects
    423
    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)
    614
    From 65 to 84 years
    594
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 2064 patients were screened, of whom 1216 patients were randomized to QVA149 110/50 µg o.d., tiotropium 18 µg o.d., or placebo. Of the 1216, one patient was randomized but not treated. One patient of the 1216 was randomized but did not receive treatment

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 QVA149
    Arm description
    		 110/50 µg capsules for inhalation, o.d
    Arm type
    		 Experimental

    Investigational medicinal product name
    indacaterol/glycopyrronium
    Investigational medicinal product code
    QVA149
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    capsules for oral inhalation

    Arm title
    		 Tiotropium
    Arm description
    		 18 μg capsules for inhalation, o.d
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tiotropium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    18 μg capsules for inhalation

    Arm title
    		 Placebo
    Arm description
    		 To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Inhalation use
    Dosage and administration details
    To match tiotropium capsules for inhalation

    Number of subjects in period 1
    		QVA149 Tiotropium Placebo
    Started
    407
    405
    404
    Randomized set (RAN)
    407
    405
    404
    Full analysis set (FAS)
    407
    405
    403
    Completed
    348
    354
    320
    Not completed
    59
    51
    84
         Adverse event, serious fatal
    4
    2
    1
         Consent withdrawn by subject
    12
    10
    20
         Adverse event, non-fatal
    27
    22
    26
         Unsatisfactory therapeutic effect
    9
    8
    27
         Protocol deviation
    4
    3
    3
         Administrative problems
    1
    4
    4
         Abnormal laboratory value
    1
    1
    -
         Lost to follow-up
    1
    -
    -
         Abnormal test procedure result(s)
    -
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 110/50 µg capsules for inhalation, o.d

    Reporting group title
    Tiotropium
    Reporting group description
    		 18 μg capsules for inhalation, o.d

    Reporting group title
    Placebo
    Reporting group description
    		 To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d

    Reporting group values
    		 QVA149 Tiotropium Placebo Total
    Number of subjects
    		 407 405 404 1216
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 205 215 194 614
        From 65-84 years
    		 199 187 208 594
        85 years and over
    		 3 3 2 8
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.6 ( 7.89 ) 64.1 ( 8.57 ) 64.9 ( 7.95 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 119 105 94 318
        Male
    		 288 300 310 898

    End points

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    End points reporting groups
    Reporting group title
    QVA149
    Reporting group description
    		 110/50 µg capsules for inhalation, o.d

    Reporting group title
    Tiotropium
    Reporting group description
    		 18 μg capsules for inhalation, o.d

    Reporting group title
    Placebo
    Reporting group description
    		 To match QVA149 capsules for inhalation, o.d To match tiotropium capsules for inhalation, o.d

    Primary: Number of patients with serious adverse events

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    End point title
    		 Number of patients with serious adverse events [1]
    End point description
    The overall rate of serious adverse events reported from initiation through 30 days post last dose. No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this primary outcome
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    407
    403
    402
    Units: Participants
    55
    55
    50
    No statistical analyses for this end point

    Secondary: Percentage of patients with composite endpoint of all-cause mortality, and serious cardio- and cerebrovascular (CCV) events.

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    End point title
    		 Percentage of patients with composite endpoint of all-cause mortality, and serious cardio- and cerebrovascular (CCV) events.
    End point description
    The endpoint of all-cause mortality and serious CCV events (composite) was chosen to further characterize any discernible risks. The patients with an event in the analysis were those who had at least one of the 2 events namely, all-cause mortality and serious CCV, during treatment or within 30 days after the date of last dose of study drug.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    407
    405
    403
    Units: Percentage of participants
        number (not applicable)
    3.9
    2
    1
    No statistical analyses for this end point

    Secondary: Post-hoc analysis: Percentage of patients with composite endpoint of cardiovascular death and MACE

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    End point title
    		 Post-hoc analysis: Percentage of patients with composite endpoint of cardiovascular death and MACE
    End point description
    The composite endpoint included all deaths and all serious CCV events, including MACE and events which were not considered MACE. A rigorous post hoc analysis was done on composite endpoint of CV deaths and major adverse cardiovascular events (MACE). The patients with an event in the analysis were those who had at least one of the 2 events namely, CV deaths and MACE, during treatment or within 30 days after the date of last dose of study drug.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    407
    405
    403
    Units: Percentage of participants
        number (not applicable)
    1
    0.7
    0.7
    No statistical analyses for this end point

    Secondary: Change from baseline in Pre-Dose forced expiratory volume over in second (FEV1)

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    End point title
    		 Change from baseline in Pre-Dose forced expiratory volume over in second (FEV1)
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards. Baseline FEV1 was defined as the average of the pre-dose FEV1 measured at -45 minutes (min) and -15 min at day 1.
    End point type
    Secondary
    End point timeframe
    Day 22, 43, 85, 183, 274 and 364
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    407
    405
    379
    Units: Liters
    least squares mean (standard error)
        Day 22 (n=378, 383, 361)
    0.1733 ( 0.18537 )
    0.1018 ( 0.18389 )
    -0.0148 ( 0.16758 )
        Day 43 (n=380, 375, 345)
    0.1751 ( 0.208 )
    0.0961 ( 0.18261 )
    -0.0196 ( 0.18178 )
        Day 85 (n=373, 373, 340)
    0.1752 ( 0.20198 )
    0.0785 ( 0.19606 )
    -0.0506 ( 0.19369 )
        Day 183 (n=356, 358, 314)
    0.1557 ( 0.21754 )
    0.0714 ( 0.20358 )
    -0.0583 ( 0.20305 )
        Day 274 (n=343, 351, 303)
    0.1463 ( 0.21424 )
    0.075 ( 0.21489 )
    -0.0601 ( 0.20936 )
        Day 364 (n=333, 346, 297)
    0.1468 ( 0.22933 )
    0.0559 ( 0.22433 )
    -0.0826 ( 0.21443 )
    No statistical analyses for this end point

    Secondary: Change from baseline in health status as measured by St. George's Respiratory Questionnaire for COPD patients (SGRQ-C)

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    End point title
    		 Change from baseline in health status as measured by St. George's Respiratory Questionnaire for COPD patients (SGRQ-C)
    End point description
    The SGRQ-C contains 40 items divided into two parts covering three aspects of health related to COPD: Part I covers "Symptoms" and is concerned with respiratory symptoms, their frequency and severity; Part II covers "Activity" and is concerned with activities that cause or are limited by breathlessness; Part II is also concerned with "Impacts" which covers a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. A score will be calculated for each of these three subscales and a "Total" score will also be calculated. In each case the lowest possible value is zero and the highest 100. Higher values correspond to greater impairment of health status.
    End point type
    Secondary
    End point timeframe
    Measurment at day 364
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    343
    349
    314
    Units: Score
        arithmetic mean (standard deviation)
    -6.79 ( 12.611 )
    -6.12 ( 13.695 )
    -2.18 ( 13.311 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Daily, morning and evening symptom scores

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    End point title
    		 Change from baseline in Daily, morning and evening symptom scores
    End point description
    Patients will be provided with an electronic diary (eDiary) to record daily clinical symptoms, or rescue medication. The patients will be instructed to routinely complete the patient diary twice daily. There are 9 total symptom questions for a total possible score of 27 at each timepoint. A higher score means the patient is reporting more symptoms related to Chronic Obstructive Pulmonary Disease. The mean daily total symptom score, the mean daytime total symptom score and the mean nighttime total symptom score were calculated for each patient over 52 weeks. Diary data recorded during the 14 day run-in period were used to calculate the baseline.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    407
    405
    403
    Units: Score
    arithmetic mean (standard deviation)
        Daily total symptom score (n=395, 395, 385)
    -1.3478 ( 1.91692 )
    -1.2283 ( 1.93241 )
    -0.7683 ( 1.73598 )
        Daytime total symptom score (n= 380, 385, 374)
    -1.1688 ( 1.9335 )
    -1.0669 ( 1.90366 )
    -0.5641 ( 1.62577 )
        Nighttime total symptom score (n= 387, 388, 375)
    -0.9731 ( 1.96898 )
    -0.9532 ( 1.78168 )
    -0.5984 ( 1.73356 )
    No statistical analyses for this end point

    Secondary: Change from baseline in percentage of nights with ‘no nighttime awakenings

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    End point title
    		 Change from baseline in percentage of nights with ‘no nighttime awakenings
    End point description
    A night with ‘no nighttime awakenings’ is defined from diary data as any night where the patient did not wake up due to symptoms.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    387
    388
    375
    Units: Percentage of nights
        arithmetic mean (standard deviation)
    11.34 ( 30.115 )
    10.66 ( 26.579 )
    8.21 ( 28.002 )
    No statistical analyses for this end point

    Secondary: Change from baseline in percentage of no daytime symptoms

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    End point title
    		 Change from baseline in percentage of no daytime symptoms
    End point description
    A day with ‘no daytime symptoms’ is defined from the diary data as any day where the patient has recorded in the evening no cough, no wheeze, no production of sputum and no feeling of breathlessness (other than when running) during the past 12 hours (approx. 8 am to 8 pm).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    380
    385
    374
    Units: Percentage of days
        arithmetic mean (standard deviation)
    5.56 ( 19.67 )
    4.72 ( 15.942 )
    1.78 ( 15.733 )
    No statistical analyses for this end point

    Secondary: Change from baseline in percentage of days able to perform usual daily activities.

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    End point title
    		 Change from baseline in percentage of days able to perform usual daily activities.
    End point description
    A day able to perform usual daily activities’ is defined from diary data as any day where the patient was not prevented from performing their usual daily activities due to respiratory symptoms.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    380
    385
    374
    Units: Percentage of days
        arithmetic mean (standard deviation)
    10.79 ( 31.006 )
    6.54 ( 30.215 )
    1.13 ( 25.039 )
    No statistical analyses for this end point

    Secondary: Change from baseline in 1 hour post-dose Forced vital capacity (FVC) measurements

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    End point title
    		 Change from baseline in 1 hour post-dose Forced vital capacity (FVC) measurements
    End point description
    Pulmonary function assessments were performed using centralized spirometry according to international standards
    End point type
    Secondary
    End point timeframe
    Day 1, 22, 43, 85, 183, 274 and 364
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    407
    405
    403
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1(n=403, 402, 399)
    0.3331 ( 0.30312 )
    0.2806 ( 0.28293 )
    0.063 ( 0.22884 )
        Day 22 (n=384, 381, 362)
    0.3971 ( 0.40009 )
    0.3123 ( 0.36755 )
    0.0178 ( 0.33624 )
        Day 43 (n=380, 373, 351)
    0.4021 ( 0.42797 )
    0.2966 ( 0.37124 )
    0.0274 ( 0.35681 )
        Day 85 (376, 371, 345)
    0.4169 ( 0.42175 )
    0.2867 ( 0.40131 )
    0.0035 ( 0.36897 )
        Day 183 (n=364, 359, 317)
    0.388 ( 0.45342 )
    0.2822 ( 0.39781 )
    -0.0283 ( 0.36919 )
        Day 274 (n=349, 352, 306)
    0.3582 ( 0.43072 )
    0.2821 ( 0.40546 )
    -0.0404 ( 0.37777 )
        Day 364 (n= 336, 347, 302)
    0.3153 ( 0.4656 )
    0.2224 ( 0.40778 )
    -0.0498 ( 0.39908 )
    No statistical analyses for this end point

    Secondary: Time to premature discontinuation

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    End point title
    		 Time to premature discontinuation
    End point description
    Time to premature treatment discontinuation for each treatment group was displayed using a Kaplan-Meier curve. The date of last dose of study medication was considered as the event date and also as the censoring date for those patients who did not discontinue treatment early. The range of the ‘time to treatment discontinuation’ varied from 5-407 days in the Tiotropium group. Hence the model estimated lower limit of the median time to treatment discontinuation is greater than the scheduled treatment period of 52 weeks.
    End point type
    Secondary
    End point timeframe
    Time varied from 5 - 407 days
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    407
    405
    403
    Units: Days
        median (confidence interval 95%)
    9999 (-9999 to 9999)
    9999 (-9999 to 9999)
    9999 (-9999 to 9999)
    No statistical analyses for this end point

    Secondary: Change from baseline in 1 hour post-dose FEV1 measurements

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    End point title
    		 Change from baseline in 1 hour post-dose FEV1 measurements
    End point description
    The avg 60 min post dose forced expiratory volume in 1 second (FEV1) at visit 4, 5, 6, 7, 8 and 9 will be analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1, 22, 43, 85, 183, 274 and 364
    End point values
    		 QVA149 Tiotropium Placebo
    Number of subjects analysed
    407
    405
    403
    Units: Liters
    arithmetic mean (standard deviation)
        Day 1 (n=403, 402, 399)
    0.2064 ( 0.14248 )
    0.1567 ( 0.13349 )
    0.0281 ( 0.11123 )
        Day 22 (n=384, 381, 362)
    0.2883 ( 0.21074 )
    0.2077 ( 0.20027 )
    1.5827 ( 15.6999 )
        Day 43 (n=380, 373, 351)
    0.2904 ( 0.23377 )
    0.2008 ( 0.20752 )
    1.6209 ( 16.89209 )
        Day 85 (n=376, 371, 345)
    0.3026 ( 0.2326 )
    0.1913 ( 0.23274 )
    -0.0217 ( 0.20195 )
        Day 183 (n=364, 359, 317)
    0.286 ( 0.24351 )
    0.1842 ( 0.22851 )
    -0.0253 ( 0.21129 )
        Day 274 (n=349, 352, 306)
    0.2749 ( 0.24314 )
    0.1681 ( 0.23626 )
    -0.036 ( 0.21854 )
        Day 364 (n= 336, 347, 302)
    0.2619 ( 0.25967 )
    0.1621 ( 0.23922 )
    -0.0533 ( 0.2156 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Tiotropium 18 µg o.d.
    Reporting group description
    		 Tiotropium 18 µg o.d.

    Reporting group title
    QVA149 110/50 µg o.d.
    Reporting group description
    		 QVA149 110/50 µg o.d.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Tiotropium 18 µg o.d. QVA149 110/50 µg o.d. Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 405 (13.58%)
    55 / 407 (13.51%)
    50 / 403 (12.41%)
         number of deaths (all causes)
    5
    8
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Adenolipoma
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         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
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Gastric cancer
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Hepatic cancer
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypopharyngeal cancer
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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 / 405 (0.25%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 407 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant mediastinal neoplasm
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 407 (0.00%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Metastases to bone
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Metastatic neoplasm
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 405 (0.49%)
    2 / 407 (0.49%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Hypertension
         subjects affected / exposed
    0 / 405 (0.00%)
    3 / 407 (0.74%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular vein distension
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial disorder
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    18 / 405 (4.44%)
    20 / 407 (4.91%)
    23 / 403 (5.71%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 23
    1 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cough
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Dyspnoea
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Dyspnoea exertional
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Haemoptysis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 405 (0.74%)
    0 / 407 (0.00%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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 fibrosis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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 failure
         subjects affected / exposed
    1 / 405 (0.25%)
    3 / 407 (0.74%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         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
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         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
    Arteriogram coronary
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Transaminases increased
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         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
    Acetabulum fracture
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Fibula fracture
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Laceration
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Ligament sprain
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Lower limb fracture
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Rib fracture
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Tibia fracture
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 407 (0.00%)
    0 / 403 (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
    Toxicity to various agents
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 407 (0.49%)
    0 / 403 (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 disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 407 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 405 (0.00%)
    3 / 407 (0.74%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 407 (0.49%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 407 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 407 (0.49%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    3 / 405 (0.74%)
    1 / 407 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Myocardial infarction
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Radiculitis
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    VIth nerve paresis
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Cataract
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 407 (0.00%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal mass
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         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
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 407 (0.25%)
    0 / 403 (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
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Mesenteric artery thrombosis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pancreatitis haemorrhagic
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Umbilical hernia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Bile duct stone
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 407 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Hepatic mass
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Liver injury
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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 failure acute
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 407 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Synovitis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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 abscess
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Bronchopneumonia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 407 (0.25%)
    0 / 403 (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
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Influenza
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 407 (0.00%)
    0 / 403 (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
    Lobar pneumonia
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 407 (0.00%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    6 / 405 (1.48%)
    3 / 407 (0.74%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 407 (0.49%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 405 (0.00%)
    0 / 407 (0.00%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    2 / 403 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 405 (0.25%)
    2 / 407 (0.49%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 407 (0.00%)
    0 / 403 (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
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 407 (0.49%)
    0 / 403 (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
    Malnutrition
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    0 / 403 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 407 (0.25%)
    1 / 403 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tiotropium 18 µg o.d. QVA149 110/50 µg o.d. Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    286 / 405 (70.62%)
    285 / 407 (70.02%)
    297 / 403 (73.70%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    274 / 405 (67.65%)
    269 / 407 (66.09%)
    287 / 403 (71.22%)
         occurrences all number
    1009
    948
    1072
    Cough
         subjects affected / exposed
    21 / 405 (5.19%)
    17 / 407 (4.18%)
    18 / 403 (4.47%)
         occurrences all number
    25
    18
    21
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    14 / 405 (3.46%)
    22 / 407 (5.41%)
    19 / 403 (4.71%)
         occurrences all number
    18
    32
    29
    Nasopharyngitis
         subjects affected / exposed
    31 / 405 (7.65%)
    33 / 407 (8.11%)
    26 / 403 (6.45%)
         occurrences all number
    39
    44
    34
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 405 (5.43%)
    18 / 407 (4.42%)
    18 / 403 (4.47%)
         occurrences all number
    28
    22
    32
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    28 / 405 (6.91%)
    27 / 407 (6.63%)
    25 / 403 (6.20%)
         occurrences all number
    32
    35
    30

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
    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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