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    Clinical Trial Results:
    A multicentre, international, randomised, parallel group, double blind study to evaluate Cardiovascular safety of linagliptin versus glimepiride in patients with type 2 diabetes mellitus at high cardiovascular risk. The CAROLINA Trial.

    Summary
    EudraCT number
    		 2009-013157-15
    Trial protocol
    		 BE   FR   DE   PT   CZ   ES   IE   FI   SE   GB   SK   IT   GR   BG  
    Global end of trial date
    21 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Sep 2019
    First version publication date
    06 Sep 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1218.74
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01243424
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.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
    27 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate non-inferiority of treatment with linagliptin in comparison with glimepiride (predominantly on metformin background treatment) with respect to time to first occurrence of any of the adjudicated components of the primary composite endpoint, i.e. CV death, non-fatal stroke, or non-fatal myocardial infarction (MI) in patients with T2DM.
    Protection of trial subjects
    Only patients that met all the study inclusion and none of the exclusion criteria were to be randomized in the study. All patients were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all patients was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Nov 2010
    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
    Slovakia: 70
    Country: Number of subjects enrolled
    South Africa: 197
    Country: Number of subjects enrolled
    Spain: 299
    Country: Number of subjects enrolled
    Sweden: 295
    Country: Number of subjects enrolled
    Switzerland: 14
    Country: Number of subjects enrolled
    Taiwan: 265
    Country: Number of subjects enrolled
    Tunisia: 47
    Country: Number of subjects enrolled
    Ukraine: 254
    Country: Number of subjects enrolled
    United Kingdom: 139
    Country: Number of subjects enrolled
    United States: 2401
    Country: Number of subjects enrolled
    Argentina: 473
    Country: Number of subjects enrolled
    Australia: 82
    Country: Number of subjects enrolled
    Belgium: 151
    Country: Number of subjects enrolled
    Brazil: 423
    Country: Number of subjects enrolled
    Bulgaria: 76
    Country: Number of subjects enrolled
    Canada: 152
    Country: Number of subjects enrolled
    Chile: 87
    Country: Number of subjects enrolled
    Colombia: 253
    Country: Number of subjects enrolled
    Czech Republic: 141
    Country: Number of subjects enrolled
    Finland: 287
    Country: Number of subjects enrolled
    France: 176
    Country: Number of subjects enrolled
    Georgia: 307
    Country: Number of subjects enrolled
    Germany: 658
    Country: Number of subjects enrolled
    Greece: 45
    Country: Number of subjects enrolled
    Hong Kong: 141
    Country: Number of subjects enrolled
    Hungary: 224
    Country: Number of subjects enrolled
    India: 322
    Country: Number of subjects enrolled
    Ireland: 35
    Country: Number of subjects enrolled
    Israel: 148
    Country: Number of subjects enrolled
    Italy: 108
    Country: Number of subjects enrolled
    Japan: 145
    Country: Number of subjects enrolled
    Korea, Republic of: 277
    Country: Number of subjects enrolled
    Malaysia: 191
    Country: Number of subjects enrolled
    Mexico: 99
    Country: Number of subjects enrolled
    Netherlands: 405
    Country: Number of subjects enrolled
    New Zealand: 83
    Country: Number of subjects enrolled
    Norway: 217
    Country: Number of subjects enrolled
    Peru: 265
    Country: Number of subjects enrolled
    Philippines: 136
    Country: Number of subjects enrolled
    Portugal: 59
    Country: Number of subjects enrolled
    Romania: 173
    Country: Number of subjects enrolled
    Russian Federation: 163
    Country: Number of subjects enrolled
    Serbia: 123
    Worldwide total number of subjects
    10606
    EEA total number of subjects
    3558
    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)
    5479
    From 65 to 84 years
    5099
    85 years and over
    28

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was multicentre, multinational, randomised, double-blind, double-dummy, parallel group,comparator-controlled trial compared Linagliptin versus (vs.) Glimepiride, predominantly on metformin background treatment in participants with type 2 diabetes mellitus (T2DM) at elevated cardiovascular (CV) risk receiving usual care.

    Pre-assignment
    Screening details
    		 All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that all participants met all inclusion/exclusion criteria. Participants were not to be randomised to trial treatment if any one of the specific entry criteria were not met.

    Period 1
    Period 1 title
    Discontinuation From Study (Treated Set)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Carer, Data analyst, Assessor
    Blinding implementation details
    This was a double-blind trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Linagliptin
    Arm description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3028, 5 participants entered/randomised to Linagliptin were not treated. Although 3023 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose, up to an estimated 432 weeks treatment period.

    Arm title
    		 Glimepiride
    Arm description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3014, 4 participants entered/randomised to Glimepiride were not treated. Although 3010 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose, up to an estimated 432 weeks treatment period.

    Number of subjects in period 1 [1]
    		Linagliptin Glimepiride
    Started
    3023
    3010
    Completed
    2899
    2895
    Not completed
    124
    115
         LostToFollowUpfor3P−MACE(StatusAlive
    38
    35
         Consent Withdrawn (Status Unknown)
    14
    12
         Site Closure (Status Alive)
    15
    22
         Site Closure (Status Unknown)
    -
    1
         LostToFollowUpfor3P−MACE(StatusUnknown)
    8
    8
         Consent Withdrawn (Status Alive)
    49
    37
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.
    Period 2
    Period 2 title
    Discontinuation From Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    This was a double-blind trial.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Linagliptin
    Arm description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3028, 5 participants entered/randomised to Linagliptin were not treated. Although 3023 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Linagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose, up to an estimated 432 weeks treatment period.

    Arm title
    		 Glimepiride
    Arm description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3014, 4 participants entered/randomised to Glimepiride were not treated. Although 3010 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose, up to an estimated 432 weeks treatment period.

    Number of subjects in period 2
    		Linagliptin Glimepiride
    Started
    3023
    3010
    Completed
    1896
    1832
    Not completed
    1127
    1178
         Consent withdrawn by subject
    309
    328
         Adverse event, non-fatal
    457
    523
         Other than listed above
    230
    211
         Lost to follow-up
    24
    28
         Protocol deviation
    46
    47
         Lack of efficacy
    61
    41

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Linagliptin
    Reporting group description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3028, 5 participants entered/randomised to Linagliptin were not treated. Although 3023 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.

    Reporting group title
    Glimepiride
    Reporting group description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3014, 4 participants entered/randomised to Glimepiride were not treated. Although 3010 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.

    Reporting group values
    		 Linagliptin Glimepiride Total
    Number of subjects
    		 3023 3010
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set (TS): All patients treated with at least one dose of trial drug.
    Units: years
        arithmetic mean (standard deviation)
    		 63.9 ( 9.5 ) 64.2 ( 9.5 ) -
    Sex: Female, Male
    TS
    Units: Subjects
        Female
    		 1185 1229 2414
        Male
    		 1838 1781 3619
    Race (NIH/OMB)
    TS
    Units: Subjects
        American Indian or Alaska Native
    		 106 108 214
        Asian
    		 531 530 1061
        Native Hawaiian or Other Pacific Islander
    		 5 3 8
        Black or African American
    		 155 169 324
        White
    		 2217 2190 4407
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 9 10 19
    Ethnicity (NIH/OMB)
    TS
    Units: Subjects
        Hispanic or Latino
    		 519 513 1032
        Not Hispanic or Latino
    		 2495 2487 4982
        Unknown or Not Reported
    		 9 10 19

    End points

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    End points reporting groups
    Reporting group title
    Linagliptin
    Reporting group description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3028, 5 participants entered/randomised to Linagliptin were not treated. Although 3023 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.

    Reporting group title
    Glimepiride
    Reporting group description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3014, 4 participants entered/randomised to Glimepiride were not treated. Although 3010 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.
    Reporting group title
    Linagliptin
    Reporting group description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3028, 5 participants entered/randomised to Linagliptin were not treated. Although 3023 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.

    Reporting group title
    Glimepiride
    Reporting group description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. Actual number of participants started is 3014, 4 participants entered/randomised to Glimepiride were not treated. Although 3010 were reported to ensure consistent reporting with baseline characteristics that includes only treated participants.

    Subject analysis set title
    Linagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.

    Subject analysis set title
    Glimepiride
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.

    Subject analysis set title
    Linagliptin
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.

    Subject analysis set title
    Glimepiride
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.

    Primary: The first 3-point Major Adverse Cardiovascular Events (3P−MACE)

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    End point title
    		 The first 3-point Major Adverse Cardiovascular Events (3P−MACE)
    End point description
    The first occurrence of any of the following Clinical Event Committee (CEC) confirmed adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), or nonfatal stroke is presented. Treated set (TS): All patients treated with at least one dose of trial drug.
    End point type
    Primary
    End point timeframe
    From randomization until individual day of trial completion, up to 432 weeks
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3023 [1]
    3010 [2]
    Units: Incidence rate/ 1000 patients-years
        number (not applicable)
    20.7
    21.2
    Notes
    [1] - TS
    [2] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the first step in a pre-defined hierarchical testing approach. The upper bound of the confidence interval (CI) of the Hazard ratio (HR) of linagliptin vs. glimepiride was compared with this noninferiority margin for the testing of non-inferiority. All non-inferiority tests were based on a margin of 1.3.
    Comparison groups
    Glimepiride v Linagliptin
    Number of subjects included in analysis
    6033
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95.47%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.14
    Notes
    [3] - Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride.
    [4] - P-values derived from Wald´s Chi-square test for non-inferiority were calculated.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    This was the second step in a pre-defined hierarchical testing approach.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    6033
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.3813 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95.47%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.14
    Notes
    [5] - Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride.
    [6] - P-values derived from Wald´s Chi-square test.

    Secondary: The first 4P−MACE

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    End point title
    		 The first 4P−MACE
    End point description
    The first key secondary endpoint was time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI), or hospitalisation for unstable angina pectoris.
    End point type
    Secondary
    End point timeframe
    From randomization until individual day of trial completion, up to 432 weeks
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3023 [7]
    3010 [8]
    Units: Incidence rate/ 1000 patients-years
        number (not applicable)
    23.4
    23.7
    Notes
    [7] - TS
    [8] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the third step in a pre-defined hierarchical testing approach.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    6033
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.4334 [10]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95.47%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.14
    Notes
    [9] - Cox proportional-hazard model with factor treatment was applied to compare linagliptin with glimepiride.
    [10] - P-values derived from Wald´s Chi-square test.

    Secondary: Percentage of participants taking trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, without >2% weight gain, and without moderate/severe hypoglycaemic episodes during maintenance phase

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    End point title
    		 Percentage of participants taking trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, without >2% weight gain, and without moderate/severe hypoglycaemic episodes during maintenance phase
    End point description
    The second key secondary endpoint was a composite endpoint of treatment sustainability, defined as the percentage of patients taking trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, without >2% weight gain, and without moderate/severe hypoglycaemic episodes during maintenance phase. TS without duplicates (TS w/o duplicates), patients who are off-drug or died prior to regular study stop were handled as non-completers considered failure (NCF).
    End point type
    Secondary
    End point timeframe
    From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3014 [11]
    3000 [12]
    Units: Percentage of participants (%)
        number (confidence interval 95%)
    16.0 (14.7 to 17.3)
    10.2 (9.1 to 11.3)
    Notes
    [11] - TS w/o duplicates (NCF)
    [12] - TS w/o duplicates (NCF)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    6014
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.0001 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.68
    Confidence interval
         level
    		 95.47%
         sides
    2-sided
         lower limit
    		 1.43
         upper limit
    		 1.96
    Notes
    [13] - Odds ratio and confidence interval are based on logistic regression with factor for treatment.
    [14] - p−value derived from chi−square test.

    Secondary: Percentage of participants who were on trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, and without >2% weight gain during maintenance phase

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    End point title
    		 Percentage of participants who were on trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, and without >2% weight gain during maintenance phase
    End point description
    The third key secondary endpoint was a composite endpoint of treatment sustainability, defined as percentage of patients who were on trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, and without >2% weight gain during maintenance phase.
    End point type
    Secondary
    End point timeframe
    From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3014 [15]
    3000 [16]
    Units: Percentage of participants (%)
        number (confidence interval 95%)
    17.4 (16.1 to 18.8)
    14.1 (12.9 to 15.4)
    Notes
    [15] - TS w/o duplicates (NCF)
    [16] - TS w/o duplicates (NCF)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the fifth step in a pre-defined hierarchical testing approach.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    6014
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.0004 [18]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.29
    Confidence interval
         level
    		 95.47%
         sides
    2-sided
         lower limit
    		 1.11
         upper limit
    		 1.48
    Notes
    [17] - Odds ratio and confidence interval are based on logistic regression with factor for treatment.
    [18] - p−value derived from logistic regression.

    Secondary: Percentage of participants with the occurrence of at least one event of 3P-MACE

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    End point title
    		 Percentage of participants with the occurrence of at least one event of 3P-MACE
    End point description
    Occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and non-fatal stroke is presented as secondary CV endpoint.
    End point type
    Secondary
    End point timeframe
    From randomization until individual day of trial completion, up to 432 weeks
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3023 [19]
    3010 [20]
    Units: Percentage of participants (%)
        number (confidence interval 95%)
    11.8 (10.7 to 13.0)
    12.0 (10.9 to 13.2)
    Notes
    [19] - TS
    [20] - TS
    No statistical analyses for this end point

    Secondary: Percentage of participants with the occurrence of at least one event of 4P -MACE

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    End point title
    		 Percentage of participants with the occurrence of at least one event of 4P -MACE
    End point description
    Occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke, and hospitalisation for unstable angina pectoris is presented as secondary CV endpoint.
    End point type
    Secondary
    End point timeframe
    From randomization until individual day of trial completion, up to 432 weeks
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3023 [21]
    3010 [22]
    Units: Percentage of participants (%)
        number (confidence interval 95%)
    13.2 (12.0 to 14.4)
    13.3 (12.2 to 14.6)
    Notes
    [21] - TS
    [22] - TS
    No statistical analyses for this end point

    Secondary: Percentage of participants with occurrence of any of the components of the composite endpoint of all adjudication-confirmed events

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    End point title
    		 Percentage of participants with occurrence of any of the components of the composite endpoint of all adjudication-confirmed events
    End point description
    Percentage of participants with occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: - CV death (including fatal stroke and fatal MI) - non-fatal MI - non-fatal stroke - hospitalisation for unstable angina pectoris - TIA - hospitalisation for heart failure - hospitalisation for coronary revascularisation procedures (CABG, PCI)
    End point type
    Secondary
    End point timeframe
    From start of the treatment until 7 days after the end of treatment, up to 433 weeks
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3023 [23]
    3010 [24]
    Units: Percentage of participants (%)
        number (confidence interval 95%)
    17.1 (15.8 to 18.5)
    17.8 (16.4 to 19.2)
    Notes
    [23] - TS
    [24] - TS
    No statistical analyses for this end point

    Secondary: Time to first occurrence of any of the components of the composite endpoint of all adjudication-confirmed events

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    End point title
    		 Time to first occurrence of any of the components of the composite endpoint of all adjudication-confirmed events
    End point description
    Time to first occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: - CV death (including fatal stroke and fatal MI) - non-fatal MI - non-fatal stroke - hospitalisation for unstable angina pectoris - Transient ischaemic attack (TIA) - hospitalisation for heart failure - hospitalisation for coronary revascularisation procedures (CABG, PCI)
    End point type
    Secondary
    End point timeframe
    From start of the treatment until 7 days after the end of treatment, up to 433 weeks
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3023 [25]
    3010 [26]
    Units: Incidence rate/ 1000 patients-years
        number (not applicable)
    31.1
    32.4
    Notes
    [25] - TS
    [26] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the fifth step in a pre-defined hierarchical testing approach.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    6033
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.5249 [28]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.09
    Notes
    [27] - Hazard ratio and confidence interval derived from Cox regression with factor treatment.
    [28] - p−value derived from Wald´s chi−square test.

    Secondary: Change from baseline to final visit in hemoglobin A1c (HbA1c)

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    End point title
    		 Change from baseline to final visit in hemoglobin A1c (HbA1c)
    End point description
    Change from baseline to final visit in HbA1c is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment. TS_D observed cases - ALL (OC-ALL): All available data were considered, including values obtained on treatment and post-treatment. Missing data were not replaced. Any values taken after rescue medication intake were kept.
    End point type
    Secondary
    End point timeframe
    Baseline and week 432
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    2951 [29]
    2949 [30]
    Units: Percentage (%)
        least squares mean (standard error)
    0.06 ( 0.02 )
    0.15 ( 0.02 )
    Notes
    [29] - TS w/o duplicates considering all available data
    [30] - TS w/o duplicates considering all available data
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the fifth step in a pre-defined hierarchical testing approach. The Analysis of Covariance (ANCOVA) model includes the fixed categorical effect of treatment and the continuous covariate of baseline HbA1c.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    5900
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.0023
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 -0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [31] - Mean difference = Linagliptin mean – Glimepiride mean

    Secondary: Change from baseline to final visit in fasting plasma glucose (FPG)

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    End point title
    		 Change from baseline to final visit in fasting plasma glucose (FPG)
    End point description
    Change from baseline to final visit in fasting plasma glucose (FPG) is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 432
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    2996 [32]
    2949 [33]
    Units: Milligram/ deciliter (mg/dL)
        least squares mean (standard error)
    12.4 ( 0.9 )
    19.7 ( 0.9 )
    Notes
    [32] - TS w/o duplicates considering all available data
    [33] - TS w/o duplicates considering all available data
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the fifth step in a pre-defined hierarchical testing approach. The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline FPG.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    5945
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.7
         upper limit
    		 -4.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.2
    Notes
    [34] - Mean difference = Linagliptin mean – Glimepiride mean

    Secondary: Change from baseline to final visit fasting total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol

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    End point title
    		 Change from baseline to final visit fasting total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol
    End point description
    Change from baseline to final visit in fasting total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment. TS_D observed cases– rescue observed cases (OC-ROC): Only the available data that were observed while patients were on trial medication (defined as time from first drug intake until last permanent treatment stop date plus the endpoint specific follow-up time) were considered.
    End point type
    Secondary
    End point timeframe
    Baseline and week 432
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3014 [35]
    3000 [36]
    Units: mg/dL
    least squares mean (standard error)
        LDL cholesterol
    -6.1 ( 0.6 )
    -6.5 ( 0.6 )
        HDL cholesterol
    0.7 ( 0.2 )
    0.3 ( 0.2 )
        Total cholesterol
    -5.4 ( 0.7 )
    -0.5 ( 0.7 )
    Notes
    [35] - TS w/o duplicates, participants on treatment
    [36] - TS w/o duplicates, participants on treatment
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LDL cholesterol. This was the fifth step in a pre-defined hierarchical testing approach. The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline LDL cholesterol.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    6014
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 = 0.64
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.4
    Confidence interval
         level
    		 95.47%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.9
    Notes
    [37] - Mean difference = Linagliptin mean – Glimepiride mean
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    HDL cholesterol. This was the fifth step in a pre-defined hierarchical testing approach. The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline HDL cholesterol.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    6014
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    P-value
    		 = 0.0497
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2
    Notes
    [38] - Mean difference = Linagliptin mean – Glimepiride mean
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Total cholesterol. This was the fifth step in a pre-defined hierarchical testing approach. The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline total cholesterol.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    6014
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 = 0.6823
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1
    Notes
    [39] - Mean difference = Linagliptin mean – Glimepiride mean

    Secondary: Change from baseline to final visit in triglycerides

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    End point title
    		 Change from baseline to final visit in triglycerides
    End point description
    Change from baseline to final visit in triglycerides is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 432
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    2788 [40]
    2762 [41]
    Units: mg/dL
        least squares mean (standard error)
    1.7 ( 2.2 )
    5.2 ( 2.2 )
    Notes
    [40] - TS w/o duplicates, participants on treatment
    [41] - TS w/o duplicates, participants on treatment
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the fifth step in a pre-defined hierarchical testing approach. The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline triglycerides.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    5550
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    P-value
    		 = 0.2678
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.6
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1
    Notes
    [42] - Mean difference = Linagliptin mean – Glimepiride mean

    Secondary: Change from baseline to final visit in creatinine

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    End point title
    		 Change from baseline to final visit in creatinine
    End point description
    Change from baseline to final visit in creatinine is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 432
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    2917 [43]
    2898 [44]
    Units: mg/dL
        least squares mean (standard error)
    0.08 ( 0.01 )
    0.09 ( 0.01 )
    Notes
    [43] - TS w/o duplicates, participants on treatment
    [44] - TS w/o duplicates, participants on treatment
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the fifth step in a pre-defined hierarchical testing approach. The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline creatinine.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    5815
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 = 0.5165
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01
    Notes
    [45] - Mean difference = Linagliptin mean – Glimepiride mean

    Secondary: Change from baseline to final visit in estimated glomerular filtration rate (eGFR)

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    End point title
    		 Change from baseline to final visit in estimated glomerular filtration rate (eGFR)
    End point description
    Change from baseline to final visit in eGFR is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 432
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    2917 [46]
    2898 [47]
    Units: mL/minute/1.73 meter^2
        least squares mean (standard error)
    -4.0 ( 0.3 )
    -5.0 ( 0.3 )
    Notes
    [46] - TS w/o duplicates, participants on treatment
    [47] - TS w/o duplicates, participants on treatment
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the fifth step in a pre-defined hierarchical testing approach. The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline eGFR.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    5815
    Analysis specification
    Pre-specified
    Analysis type
    		 other [48]
    P-value
    		 = 0.5165
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Notes
    [48] - Mean difference = Linagliptin mean – Glimepiride mean

    Secondary: Change from baseline to final visit in urine albumin creatinine ratio (UACR)

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    End point title
    		 Change from baseline to final visit in urine albumin creatinine ratio (UACR)
    End point description
    Change from baseline to final visit in UACR is presented as secondary diabetes-related endpoint. Least square mean is adjusted gMean ratio. The Final Visit value referred to the last value obtained on-treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 432
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    2904 [49]
    2880 [50]
    Units: mg/ gcrea
        least squares mean (standard error)
    1.52 ( 1.83 )
    1.57 ( 1.83 )
    Notes
    [49] - TS w/o duplicates, participants on treatment
    [50] - TS w/o duplicates, participants on treatment
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was the fifth step in a pre-defined hierarchical testing approach. The ANCOVA model includes the fixed categorical effect of treatment and the continuous covariate of baseline UACR.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    5784
    Analysis specification
    Pre-specified
    Analysis type
    		 other [51]
    P-value
    		 = 0.2921
    Method
    		 ANCOVA
    Parameter type
    		 geometric mean (gMean) ratio (%)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.91
         upper limit
    		 1.03
    Notes
    [51] - gMean ration= Linagliptin mean/ Glimepiride mean

    Secondary: Percentage of participants with transition in albuminuria classes

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    End point title
    		 Percentage of participants with transition in albuminuria classes
    End point description
    Percentage of patients with transition in albuminuria classes is presented as secondary endpoint. Data for last value on treatment (LVOT) to baseline (base) is presented.
    End point type
    Secondary
    End point timeframe
    Baseline and week 432
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    3014 [52]
    3000 [53]
    Units: Percentage of participants (%)
    number (not applicable)
        Base (<30mg/gcrea) LVOT (<30mg/gcrea
    58.4
    57.7
        Base(<30mg/gcrea)LVOT(>=30 to<=300mg/gcrea)
    14.1
    16.0
        Base (<30 mg/gcrea) LVOT (>300 mg/gcrea)
    1.4
    1.4
        Base (>=30 to <=300 mg/gcrea) LVOT(<30mg/gcrea)
    5.4
    5.1
        Base(>=30to<=300mg/gcrea)LVOT(>=30to<=300mg/gcrea)
    12.7
    12.1
        Base (>=30 to <=300 mg/gcrea) LVOT(>300 mg/gcrea)
    3.5
    3.7
        Base (>300 mg/gcrea) LVOT (<30 mg/gcrea)
    0.1
    0.3
        Base (>300 mg/gcrea) LVOT(>=30 to<=300mg/gcrea)
    0.8
    0.9
        Base (>300 mg/gcrea) LVOT(>300 mg/gcrea)
    3.4
    2.7
    Notes
    [52] - TS w/o duplicates, participants on treatment
    [53] - TS w/o duplicates, participants on treatment
    No statistical analyses for this end point

    Secondary: Change from baseline of insulin secretion rate (ISR) at fixed glucose concentration at 208 weeks

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    End point title
    		 Change from baseline of insulin secretion rate (ISR) at fixed glucose concentration at 208 weeks
    End point description
    The endpoint change from baseline of ISR at fixed glucose concentration at 208 weeks as derived from a 3-hour meal tolerance test is Beta-cell function sub-study endpoint. Meal tolerance test(MTT) last observation carried forward(LOCF) set: Randomised and treated patients with one dose of study drug and signed the substudy Informed Consent with valid baseline and on-treatment MTT. If values taken after rescue medication intake will be set to missing, last observed ontreatment value was carry forwarded.
    End point type
    Secondary
    End point timeframe
    Baseline and week 208
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    40 [54]
    48 [55]
    Units: Picomol/ minute/meter^2 (pmol/min/m²)
        arithmetic mean (standard error)
    11.07 ( 15.07 )
    6.95 ( 13.76 )
    Notes
    [54] - MTT_LOCF
    [55] - MTT_LOCF
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The ANCOVA model includes the fixed categorical effects of treatment and the continuous covariate of baseline ISR.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other [56]
    P-value
    		 = 0.8402
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.46
         upper limit
    		 44.71
    Notes
    [56] - Mean difference= Linagliptin mean- Glimepiride mean

    Secondary: Percentage of participants with occurrence of accelerated cognitive decline at end of follow-up

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    End point title
    		 Percentage of participants with occurrence of accelerated cognitive decline at end of follow-up
    End point description
    Occurrence of accelerated cognitive decline based on RBI score at end of follow-up (a dichotomous outcome measure; presence or absence of accelerated cognitive decline) is Cognition sub-study endpoint. Full analysis set cognition(FAS-COG): Randomised and treated patients with one dose of study drug, baseline assessment (the z-scores, A&E or Minimental state examination(MMSE) can be calculated), years of formal education with baseline MMSE≥24 and at least one on-treatment assessment (of which at least one of the RBI scores can be calculated).
    End point type
    Secondary
    End point timeframe
    433 weeks
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    1618 [57]
    1545 [58]
    Units: Percentage of participants (%)
        number (confidence interval 95%)
    27.8 (25.6 to 30.0)
    27.6 (25.4 to 29.9)
    Notes
    [57] - FAS-COG
    [58] - FAS-COG
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Logistic regression model with terms for treatment as a fixed effect with Wald confidence Interval was used.
    Comparison groups
    Linagliptin v Glimepiride
    Number of subjects included in analysis
    3163
    Analysis specification
    Pre-specified
    Analysis type
    		 other [59]
    P-value
    		 = 0.9112
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.18
    Notes
    [59] - Linagliptin vs. Glimepiride odds is presented.

    Secondary: Change from baseline in the inter-quartile range of diurnal glucose variability to end of study

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    End point title
    		 Change from baseline in the inter-quartile range of diurnal glucose variability to end of study
    End point description
    The data for this endpoint of the continuous glucose monitoring sub-study was not collected and analyzed as this sub study was stopped due to low than expected recruitment rate and an increased discontinuation rate.
    End point type
    Secondary
    End point timeframe
    433 weeks
    End point values
    		 Linagliptin Glimepiride
    Number of subjects analysed
    0 [60]
    0 [61]
    Units: Percentage of participants (%)
    Notes
    [60] - The continuous glucose monitoring sub-study was stopped.
    [61] - The continuous glucose monitoring sub-study was stopped.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of the treatment until 7 days after the end of treatment, up to 433 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Linagliptin
    Reporting group description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.

    Reporting group title
    Glimepiride
    Reporting group description
    		 After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period.

    Serious adverse events
    		 Linagliptin Glimepiride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1403 / 3023 (46.41%)
    1448 / 3010 (48.11%)
         number of deaths (all causes)
    308
    336
         number of deaths resulting from adverse events
    5
    8
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute promyelocytic leukaemia
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma of appendix
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    8 / 3023 (0.26%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Adenocarcinoma pancreas
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Adenoma benign
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal neoplasm
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angiosarcoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    39 / 3023 (1.29%)
    33 / 3010 (1.10%)
         occurrences causally related to treatment / all
    0 / 49
    0 / 44
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basosquamous carcinoma of skin
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bladder cancer
         subjects affected / exposed
    4 / 3023 (0.13%)
    8 / 3010 (0.27%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer recurrent
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder papilloma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    2 / 3023 (0.07%)
    8 / 3010 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma recurrent
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    5 / 3023 (0.17%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain neoplasm benign
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    12 / 3023 (0.40%)
    9 / 3010 (0.30%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Breast cancer metastatic
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Breast cancer stage IV
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Carcinoid tumour pulmonary
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lymphoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    2 / 3023 (0.07%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    12 / 3023 (0.40%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Colon cancer metastatic
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Colon neoplasm
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctival melanoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cutaneous lymphoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysplastic naevus
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enchondromatosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    2 / 3023 (0.07%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Ependymoma benign
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Essential thrombocythaemia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrous histiocytoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder adenocarcinoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gallbladder cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric adenoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    6 / 3023 (0.20%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Gastrointestinal carcinoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal melanoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemangioma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hairy cell leukaemia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hodgkin's disease
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopharyngeal neoplasm
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal papillary mucinous neoplasm
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    3 / 3023 (0.10%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leiomyoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna recurrent
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lipoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    4 / 3023 (0.13%)
    8 / 3010 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Lung adenocarcinoma stage I
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage II
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Lung carcinoma cell type unspecified stage III
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    10 / 3023 (0.33%)
    6 / 3010 (0.20%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 6
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Lung squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung squamous cell carcinoma stage III
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytic leukaemia
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant ascites
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    7 / 3023 (0.23%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant polyp
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Meningioma
         subjects affected / exposed
    1 / 3023 (0.03%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma benign
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesothelioma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bladder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    2 / 3023 (0.07%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastases to liver
         subjects affected / exposed
    5 / 3023 (0.17%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Metastases to lung
         subjects affected / exposed
    3 / 3023 (0.10%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Metastases to lymph nodes
         subjects affected / exposed
    5 / 3023 (0.17%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastases to peritoneum
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastasis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastatic neoplasm
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Mucinous adenocarcinoma of appendix
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mycosis fungoides
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myxofibrosarcoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasopharyngeal cancer
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neoplasm prostate
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm skin
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurofibroma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-small cell lung cancer stage IV
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oral papilloma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian epithelial cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatic carcinoma
         subjects affected / exposed
    9 / 3023 (0.30%)
    9 / 3010 (0.30%)
         occurrences causally related to treatment / all
    2 / 9
    3 / 9
         deaths causally related to treatment / all
    2 / 7
    3 / 7
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 3023 (0.00%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Pancreatic carcinoma stage IV
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatic neoplasm
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paranasal sinus and nasal cavity malignant neoplasm
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 3023 (0.03%)
    6 / 3010 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Plasmacytoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural sarcoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Porocarcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prolactin-producing pituitary tumour
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    28 / 3023 (0.93%)
    29 / 3010 (0.96%)
         occurrences causally related to treatment / all
    0 / 28
    0 / 30
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 3023 (0.00%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 3023 (0.00%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer stage 0
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    4 / 3010 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    2 / 3023 (0.07%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Rectal cancer metastatic
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Refractory anaemia with ringed sideroblasts
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    3 / 3023 (0.10%)
    6 / 3010 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal cell carcinoma
         subjects affected / exposed
    6 / 3023 (0.20%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal neoplasm
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary gland neoplasm
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sebaceous carcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin angiosarcoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Small intestine adenocarcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Soft tissue sarcoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    6 / 3023 (0.20%)
    6 / 3010 (0.20%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    6 / 3023 (0.20%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    13 / 3023 (0.43%)
    16 / 3010 (0.53%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma of the hypopharynx
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the oral cavity
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma of the vulva
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thymoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell cancer of the renal pelvis and ureter
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    2 / 3023 (0.07%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour ulceration
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Uterine leiomyoma
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vipoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Waldenstrom's macroglobulinaemia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aneurysm
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    5 / 3023 (0.17%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Aortic arteriosclerosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic occlusion
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    3 / 3023 (0.10%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    1 / 3023 (0.03%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arteritis
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atherosclerotic plaque rupture
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    4 / 3023 (0.13%)
    6 / 3010 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    9 / 3023 (0.30%)
    17 / 3010 (0.56%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic vascular disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Embolism venous
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Femoral artery aneurysm
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery embolism
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    4 / 3023 (0.13%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    12 / 3023 (0.40%)
    9 / 3010 (0.30%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    15 / 3023 (0.50%)
    21 / 3010 (0.70%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 26
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Hypertensive emergency
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    5 / 3023 (0.17%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infarction
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intermittent claudication
         subjects affected / exposed
    1 / 3023 (0.03%)
    4 / 3010 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic limb pain
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    6 / 3023 (0.20%)
    12 / 3010 (0.40%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    10 / 3023 (0.33%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 3023 (0.00%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral vascular disorder
         subjects affected / exposed
    3 / 3023 (0.10%)
    4 / 3010 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    3 / 3023 (0.10%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac operation
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac pacemaker replacement
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colostomy
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colostomy closure
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary arterial stent insertion
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implantable defibrillator insertion
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    3 / 3023 (0.10%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve replacement
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic operation
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shoulder arthroplasty
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal decompression
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent placement
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroidectomy
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transurethral prostatectomy
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adhesion
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 3023 (0.10%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adverse drug reaction
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac death
         subjects affected / exposed
    7 / 3023 (0.23%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 7
    0 / 3
    Chest discomfort
         subjects affected / exposed
    3 / 3023 (0.10%)
    6 / 3010 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    50 / 3023 (1.65%)
    52 / 3010 (1.73%)
         occurrences causally related to treatment / all
    0 / 64
    0 / 59
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    20 / 3023 (0.66%)
    20 / 3010 (0.66%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 20
         deaths causally related to treatment / all
    0 / 20
    0 / 20
    Discomfort
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exercise tolerance decreased
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 3023 (0.00%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 3023 (0.10%)
    4 / 3010 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hernia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site extravasation
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site haematoma
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 3023 (0.10%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mass
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 3023 (0.03%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 6
    Non-cardiac chest pain
         subjects affected / exposed
    8 / 3023 (0.26%)
    8 / 3010 (0.27%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Puncture site haemorrhage
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 3023 (0.23%)
    8 / 3010 (0.27%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retention cyst
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    3 / 3023 (0.10%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Sudden death
         subjects affected / exposed
    9 / 3023 (0.30%)
    4 / 3010 (0.13%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 4
         deaths causally related to treatment / all
    0 / 9
    1 / 4
    Swelling
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular stent stenosis
         subjects affected / exposed
    3 / 3023 (0.10%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to vaccine
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Loss of personal independence in daily activities
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sexual abuse
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired phimosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenomyosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balanoposthitis
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    5 / 3023 (0.17%)
    19 / 3010 (0.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast pain
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erectile dysfunction
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic prolapse
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic obstruction
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatism
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    4 / 3023 (0.13%)
    4 / 3010 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    2 / 3023 (0.07%)
    4 / 3010 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvar dysplasia
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    9 / 3023 (0.30%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    8 / 3023 (0.26%)
    10 / 3010 (0.33%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Apnoea
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Asthma
         subjects affected / exposed
    5 / 3023 (0.17%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    2 / 3023 (0.07%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    23 / 3023 (0.76%)
    26 / 3010 (0.86%)
         occurrences causally related to treatment / all
    0 / 28
    0 / 49
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 3023 (0.07%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragm muscle weakness
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic paralysis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    15 / 3023 (0.50%)
    22 / 3010 (0.73%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 25
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    5 / 3023 (0.17%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    7 / 3023 (0.23%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 3023 (0.03%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    2 / 3023 (0.07%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Lung disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septum deviation
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pickwickian syndrome
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    8 / 3023 (0.26%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 3023 (0.07%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 3023 (0.10%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 3023 (0.20%)
    16 / 3010 (0.53%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 16
         deaths causally related to treatment / all
    0 / 1
    0 / 6
    Pulmonary fibrosis
         subjects affected / exposed
    3 / 3023 (0.10%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pulmonary hypertension
         subjects affected / exposed
    6 / 3023 (0.20%)
    11 / 3010 (0.37%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    5 / 3023 (0.17%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary toxicity
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    8 / 3023 (0.26%)
    14 / 3010 (0.47%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 16
         deaths causally related to treatment / all
    0 / 2
    0 / 5
    Sleep apnoea syndrome
         subjects affected / exposed
    3 / 3023 (0.10%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Snoring
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheomalacia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitated depression
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    4 / 3023 (0.13%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burnout syndrome
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 3023 (0.00%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Delirium
         subjects affected / exposed
    6 / 3023 (0.20%)
    4 / 3010 (0.13%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium tremens
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 3023 (0.10%)
    6 / 3010 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encopresis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 3023 (0.03%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    2 / 3023 (0.07%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic stress disorder
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    3 / 3023 (0.10%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient psychosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device battery issue
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device defective
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 3023 (0.03%)
    3 / 3010 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device fastener issue
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device leakage
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device loosening
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    6 / 3023 (0.20%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dyskinesia
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    20 / 3023 (0.66%)
    16 / 3010 (0.53%)
         occurrences causally related to treatment / all
    0 / 20
    1 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    9 / 3023 (0.30%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 9
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    3 / 3023 (0.10%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    20 / 3023 (0.66%)
    14 / 3010 (0.47%)
         occurrences causally related to treatment / all
    0 / 21
    1 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestatic liver injury
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cirrhosis alcoholic
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder necrosis
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder polyp
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    3 / 3023 (0.10%)
    6 / 3010 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic fibrosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic lesion
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatic mass
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    6 / 3023 (0.20%)
    5 / 3010 (0.17%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Portal vein thrombosis
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 3023 (0.20%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    3 / 3023 (0.10%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angiocardiogram
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anticoagulation drug level below therapeutic
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 3023 (0.20%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    12 / 3023 (0.40%)
    11 / 3010 (0.37%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac stress test abnormal
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Computerised tomogram head abnormal
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 3023 (0.07%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram ST segment depression
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    2 / 3023 (0.07%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram ambulatory abnormal
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Full blood count decreased
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 3023 (0.23%)
    7 / 3010 (0.23%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 3023 (0.00%)
    2 / 3010 (0.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart rate decreased
         subjects affected / exposed
    0 / 3023 (0.00%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 3023 (0.07%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis C virus test
         subjects affected / exposed
    1 / 3023 (0.03%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio decreased
         subjects affected / exposed
    1 / 3023 (0.03%)
    1 / 3010 (0.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    3 / 3023 (0.10%)
    0 / 3010 (0.00%)
         occurrences causally related to treatment / all
    0 / 3