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    Clinical Trial Results:
    A long-term, randomised, double-blind, placebo-controlled, multinational, multi-centre trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes

    Summary
    EudraCT number
    2012-002839-28
    Trial protocol
    GB   ES   BG   DE   DK   PL   IT  
    Global end of trial date
    15 Mar 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Mar 2017
    First version publication date
    31 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9535-3744
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01720446
    WHO universal trial number (UTN)
    U1111-1131-7227
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.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
    24 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm that treatment with semaglutide does not result in an unacceptable increase in cardiovascular risk as compared to placebo in adults with type 2 diabetes. This is done by demonstrating that the upper limit of the two-sided 95% confidence interval (CI) of the hazard ratio for semaglutide versus placebo is less than 1.8 when comparing time to first occurrence of a major adverse cardiovascular event (MACE).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, ICH Good Clinical Practice, EN ISO 14155 Part 1 and 2 and FDA 21 CFR 312.120.
    Background therapy
    All participating subjects received the best standard-of-care in addition to the trial products and, to the extent possible, achieved optimal glycaemic control according to local standards (additional glucose lowering medications could be added to the anti-diabetic regimen at the discretion of investigator).
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    21 Feb 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 166
    Country: Number of subjects enrolled
    Australia: 111
    Country: Number of subjects enrolled
    Bulgaria: 101
    Country: Number of subjects enrolled
    Brazil: 105
    Country: Number of subjects enrolled
    Canada: 138
    Country: Number of subjects enrolled
    Germany: 85
    Country: Number of subjects enrolled
    Denmark: 66
    Country: Number of subjects enrolled
    Algeria: 95
    Country: Number of subjects enrolled
    Spain: 85
    Country: Number of subjects enrolled
    United Kingdom: 117
    Country: Number of subjects enrolled
    Israel: 100
    Country: Number of subjects enrolled
    Italy: 80
    Country: Number of subjects enrolled
    Mexico: 165
    Country: Number of subjects enrolled
    Malaysia: 70
    Country: Number of subjects enrolled
    Poland: 98
    Country: Number of subjects enrolled
    Russian Federation: 294
    Country: Number of subjects enrolled
    Thailand: 74
    Country: Number of subjects enrolled
    Turkey: 128
    Country: Number of subjects enrolled
    Taiwan: 82
    Country: Number of subjects enrolled
    United States: 1137
    Worldwide total number of subjects
    3297
    EEA total number of subjects
    632
    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)
    1699
    From 65 to 84 years
    1578
    85 years and over
    20

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 229 sites in 20 countries. Country (sites): Algeria (4), Argentina (7), Australia (8), Brazil (8), Bulgaria (5), Canada (13), Denmark (5), Germany (7), Israel (6), Italy (6), Malaysia (6), Mexico (9), Poland (5), Russia (11), Spain (6), Taiwan (4), Thailand (5), Turkey (10), United Kingdom (8) and United States (96).

    Pre-assignment
    Screening details
    The trial population was subjects with T2D with inadequate glycaemic control (HbA1c ≥ 7%) at high CV risk. The trial included subjects ≥ 50 years of age at screening with clinical evidence of CV disease and subjects ≥ 60 years of age at screening with subclinical evidence of CV disease.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Semaglutide 0.5 mg
    Arm description
    Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Semaglutide solution for injection (1.34 mg/mL in a 1.5 mL pre-filled PDS290 pen-injector) was administered in doses of 0.5 mg once-weekly as subcutaneous (s.c.) injections either in the thigh, abdomen or upper arm, at any time of day irrespective of meals. Subjects started with doses of 0.25 mg semaglutide. After 4 weeks of treatment, the dose was escalated (doubled). Hence, the target dose of 0.5 mg was achieved after 4 weeks of treatment.

    Arm title
    Semaglutide 1.0 mg
    Arm description
    Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Semaglutide solution for injection (1.34 mg/mL in a 1.5 mL pre-filled PDS290 pen-injector) was administered in doses of 1.0 mg once-weekly as subcutaneous (s.c.) injections either in the thigh, abdomen or upper arm, at any time of day irrespective of meals. Subjects started with doses of 0.25 mg semaglutide. After 4 weeks of treatment, the dose was escalated (doubled). Hence, the target dose of 1.0 mg was achieved after 8 weeks of treatment.

    Arm title
    Placebo 0.5 mg
    Arm description
    Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The composition of the placebo corresponded to that of semaglutide drug product but with absence of the active pharmaceutical ingredient. Placebo solution for injection (1.34 mg/mL in a 1.5 mL pre-filled PDS290 pen-injector) was administered in doses of 0.5 mg once-weekly as subcutaneous (s.c.) injections either in the thigh, abdomen or upper arm, at any time of day irrespective of meals. Subjects started with doses of 0.25 mg semaglutide. After 4 weeks of treatment, the dose was escalated (doubled). Hence, the target dose of 0.5 mg was achieved after 4 weeks of treatment.

    Arm title
    Placebo 1.0 mg
    Arm description
    Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The composition of the placebo corresponded to that of semaglutide drug product but with absence of the active pharmaceutical ingredient. Placebo solution for injection (1.34 mg/mL in a 1.5 mL pre-filled PDS290 pen-injector) was administered in doses of 1.0 mg once-weekly as subcutaneous (s.c.) injections either in the thigh, abdomen or upper arm, at any time of day irrespective of meals. Subjects started with doses of 0.25 mg semaglutide. After 4 weeks of treatment, the dose was escalated (doubled). Hence, target dose of 1.0 mg was achieved after 8 weeks of treatment.

    Number of subjects in period 1
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Started
    826
    822
    824
    825
    Completed
    812
    811
    804
    805
    Not completed
    14
    11
    20
    20
         Consent withdrawn by subject
    2
    5
    4
    4
         Lost to follow-up
    12
    6
    16
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 0.5 mg
    Reporting group description
    Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.

    Reporting group title
    Semaglutide 1.0 mg
    Reporting group description
    Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.

    Reporting group title
    Placebo 0.5 mg
    Reporting group description
    Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.

    Reporting group title
    Placebo 1.0 mg
    Reporting group description
    Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.

    Reporting group values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg Total
    Number of subjects
    826 822 824 825 3297
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    440 415 419 425 1699
        From 65-84 years
    383 400 399 396 1578
        85 years and over
    3 7 6 4 20
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    64.6 ± 7.3 64.7 ± 7.1 64.8 ± 7.6 64.4 ± 7.5 -
    Gender Categorical
    Units: Subjects
        Female
    331 304 342 318 1295
        Male
    495 518 482 507 2002
    Glycosylated haemoglobin
    Units: percentage of glycosylated haemoglobin
        arithmetic mean (standard deviation)
    8.67 ± 1.39 8.73 ± 1.51 8.7 ± 1.49 8.7 ± 1.45 -
    Fasting plasma glucose
    Units: mg/dL
        arithmetic mean (standard deviation)
    185.4 ± 66.09 182.9 ± 68.04 185.8 ± 68.23 184.6 ± 63.08 -
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    91.8 ± 20.25 92.86 ± 21.05 91.83 ± 20.35 91.9 ± 20.75 -
    LDL-cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    89.62 ± 39.08 89.72 ± 34.49 89.01 ± 38.35 91.14 ± 37.9 -
    HDL-cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    45.92 ± 13 44.97 ± 12.42 45.82 ± 12.92 44.61 ± 12.26 -
    Total cholesterol
    Units: mg/dL
        geometric mean (full range (min-max))
    165.38 (65.25 to 632.43) 164.96 (79.54 to 562.16) 164.38 (70.27 to 378.38) 165.97 (64.86 to 537.07) -
    Triglycerides
    Units: mg/dL
        geometric mean (full range (min-max))
    163.66 (27.59 to 1913.5) 158.93 (10.68 to 3378.44) 162.3 (30.26 to 1438.24) 163 (35.6 to 2435.93) -
    Free fatty acids
    Units: mmol/L
        geometric mean (full range (min-max))
    0.83 (0.04 to 3.82) 0.8 (0.04 to 4.2) 0.83 (0.04 to 3.34) 0.81 (0.04 to 4.22) -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    136.1 ± 17.97 135.8 ± 16.98 135.8 ± 16.16 134.8 ± 17.45 -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    77.1 ± 9.78 76.88 ± 10.21 77.54 ± 9.85 76.66 ± 10.21 -
    Pulse rate
    Units: beats/min
        arithmetic mean (standard deviation)
    72.69 ± 11.22 71.53 ± 10.86 72.01 ± 10.62 71.95 ± 10.92 -
    Subject analysis sets

    Subject analysis set title
    Semaglutide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received once-weekly dose of semaglutide 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received once-weekly dose of placebo 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment . Each subject was treated for 104 weeks.

    Subject analysis sets values
    Semaglutide Placebo
    Number of subjects
    1648
    1649
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    64.7 ± 7.2
    64.6 ± 7.5
    Gender Categorical
    Units: Subjects
        Female
        Male
    Glycosylated haemoglobin
    Units: percentage of glycosylated haemoglobin
        arithmetic mean (standard deviation)
    ±
    ±
    Fasting plasma glucose
    Units: mg/dL
        arithmetic mean (standard deviation)
    ±
    ±
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    ±
    ±
    LDL-cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    ±
    ±
    HDL-cholesterol
    Units: mg/dL
        arithmetic mean (standard deviation)
    ±
    ±
    Total cholesterol
    Units: mg/dL
        geometric mean (full range (min-max))
    Triglycerides
    Units: mg/dL
        geometric mean (full range (min-max))
    Free fatty acids
    Units: mmol/L
        geometric mean (full range (min-max))
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    ±
    ±
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    ±
    ±
    Pulse rate
    Units: beats/min
        arithmetic mean (standard deviation)
    ±
    ±

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 0.5 mg
    Reporting group description
    Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.

    Reporting group title
    Semaglutide 1.0 mg
    Reporting group description
    Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.

    Reporting group title
    Placebo 0.5 mg
    Reporting group description
    Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.

    Reporting group title
    Placebo 1.0 mg
    Reporting group description
    Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.

    Subject analysis set title
    Semaglutide
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received once-weekly dose of semaglutide 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received once-weekly dose of placebo 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment . Each subject was treated for 104 weeks.

    Primary: Time from randomisation to first occurrence of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.

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    End point title
    Time from randomisation to first occurrence of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.
    End point description
    Proportion of subjects experiencing a first event of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke.
    End point type
    Primary
    End point timeframe
    Time from randomisation to first occurrence of an expanded composite cardiovascular outcome.
    End point values
    Semaglutide Placebo
    Number of subjects analysed
    1648
    1649
    Units: proportion of subjects
        number (not applicable)
    6.6
    8.9
    Statistical analysis title
    Non-Inferiority
    Statistical analysis description
    The primary endpoint was analysed using a stratified Cox proportional hazards model with treatment group (semaglutide, placebo) as fixed factor. Assuming the same population MACE risk for the semaglutide and placebo groups (i.e., the population HR equals 1), a total minimum of 122 events were needed in order to have at least 90% power to ascertain that the upper two-sided 95% confidence limit for the HR was less than 1.8.
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [1]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    0.95
    Notes
    [1] - The 'p-value' is for the two-sided Wald test of non-inferiority with limit 1.8.
    Statistical analysis title
    Superiority
    Statistical analysis description
    A post hoc analysis of superiority of semaglutide versus placebo was performed based on the pre-specified Cox proportional hazard analysis using the two-sided Wald test of no difference, with treatment (semaglutide, placebo) as fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0167 [2]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.58
         upper limit
    0.95
    Notes
    [2] - The 'p-value' is for the two-sided Wald test of no difference.

    Secondary: Time from randomisation to first occurrence of an expanded composite cardiovascular outcome.

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    End point title
    Time from randomisation to first occurrence of an expanded composite cardiovascular outcome.
    End point description
    Subjects experiencing first occurrence of an expanded composite CV outcome (defined as either MACE, revascularisation [coronary and peripheral], unstable angina requiring hospitalisation or hospitalisation for heart failure).
    End point type
    Secondary
    End point timeframe
    Time from randomisation up to end of follow-up (scheduled at week 109)
    End point values
    Semaglutide Placebo
    Number of subjects analysed
    1648
    1649
    Units: proportion of subject
        number (not applicable)
    12.1
    16
    Statistical analysis title
    Analysis for an expanded composite CV outcome
    Statistical analysis description
    Analysis was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0016
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    0.89

    Secondary: Time from randomisation to each individual component of the expanded composite cardiovascular outcome

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    End point title
    Time from randomisation to each individual component of the expanded composite cardiovascular outcome
    End point description
    Subjects experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as either MACE, revascularisation [coronary and peripheral], unstable angina requiring hospitalisation or hospitalisation for heart failure).
    End point type
    Secondary
    End point timeframe
    Time from randomisation up to end of Follow-up (scheduled at week 109)
    End point values
    Semaglutide Placebo
    Number of subjects analysed
    1648
    1649
    Units: proportion of subjects
    number (not applicable)
        Cardiovascular death
    1.6
    1.9
        Non-fatal MI
    2.5
    3.7
        Non-fatal Stroke
    1.5
    2.7
        Revascularisation
    2.6
    4.2
        UAP requiring hospitalisation
    1.1
    1.3
        Hospitalisation for heart failure
    2.7
    2.4
    Statistical analysis title
    Analysis for cardiovascular death
    Statistical analysis description
    Analysis for CV death was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9181
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.48
    Statistical analysis title
    Analysis for non-fatal myocardial infarction
    Statistical analysis description
    Analysis for non-fatal myocardial infarction was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1194
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1.08
    Statistical analysis title
    Analysis for non-fatal stroke
    Statistical analysis description
    Analysis for non-fatal stroke was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0438
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    0.99
    Statistical analysis title
    Analysis for revascularisation
    Statistical analysis description
    Analysis for revascularisation was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0027
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    0.86
    Statistical analysis title
    Analysis for UA requiring hospitalisation
    Statistical analysis description
    Analysis for 'unstable angina requiring hospitalisation' was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4914
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.44
    Statistical analysis title
    Analysis for hospitalisation for heart failure
    Statistical analysis description
    Analysis for hospitalisation for heart failure was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5735
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.61

    Secondary: Time from randomisation to first occurrence of all-cause death, non-fatal MI, or non-fatal stroke

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    End point title
    Time from randomisation to first occurrence of all-cause death, non-fatal MI, or non-fatal stroke
    End point description
    Proportion of subjects experiencing a first occurrence of all-cause death, non-fatal MI, or non-fatal stroke.
    End point type
    Secondary
    End point timeframe
    Time from randomisation up to end of follow-up (scheduled at week 109)
    End point values
    Semaglutide Placebo
    Number of subjects analysed
    1648
    1649
    Units: proportion of subjects
        number (not applicable)
    7.4
    9.6
    Statistical analysis title
    Analysis
    Statistical analysis description
    Analysis for all-cause death, non-fatal MI or non-fatal stroke was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
    Comparison groups
    Semaglutide v Placebo
    Number of subjects included in analysis
    3297
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0292
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    0.97

    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: glycosylated haemoglobin (HbA1c)

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    End point title
    Change from baseline to last assessment in the trial in other treatment outcomes: glycosylated haemoglobin (HbA1c)
    End point description
    Estimated mean change from baseline in glycosylated haemoglobin (HbA1c) to last assessment in the trial during the treatment period.
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: percentage of glycosylated haemoglobin
        least squares mean (standard error)
    -1.09 ± 0.05
    -1.41 ± 0.05
    -0.44 ± 0.05
    -0.36 ± 0.05
    Statistical analysis title
    Analysis for HbA1c
    Statistical analysis description
    Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    -0.52
    Statistical analysis title
    Analysis for HbA1c
    Statistical analysis description
    Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -1.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.19
         upper limit
    -0.91

    Secondary: Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: fasting plasma glucose

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    End point title
    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: fasting plasma glucose
    End point description
    Estimated mean change from baseline to last assessment in fasting plasma glucose in the trial during the treatment period.
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: mg/dL
        least squares mean (standard error)
    -1.75 ± 0.12
    -2.11 ± 0.12
    -1.02 ± 0.12
    -0.88 ± 0.12
    Statistical analysis title
    Analysis for FPG
    Statistical analysis description
    Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.06
         upper limit
    -0.38
    Statistical analysis title
    Analysis for FPG
    Statistical analysis description
    Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -1.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.56
         upper limit
    -0.88

    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: body weight

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    End point title
    Change from baseline to last assessment in the trial in other treatment outcomes: body weight [3]
    End point description
    Estimated mean change from baseline to last assessment in body weight in the trial during the treatment period.
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The data for the two placebo arms are pooled for analysis and thus there are only 3 arms for this endpoint instead of four.
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    826
    822
    1649
    Units: kg
        least squares mean (standard error)
    -3.57 ± 0.21
    -4.88 ± 0.22
    -0.62 ± 0.15
    Statistical analysis title
    Analysis for body weight
    Statistical analysis description
    Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo
    Number of subjects included in analysis
    2475
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -2.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.47
         upper limit
    -2.44
    Statistical analysis title
    Analysis for body weight
    Statistical analysis description
    Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo
    Number of subjects included in analysis
    2471
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    treatment difference
    Point estimate
    -4.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.78
         upper limit
    -3.75

    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: lipid profile

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    End point title
    Change from baseline to last assessment in the trial in other treatment outcomes: lipid profile
    End point description
    Estimated ratio to baseline at week 104 during the treatment period in lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides).
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: mg/dL
    least squares mean (standard error)
        Total cholesterol
    0.97 ± 0.01
    0.97 ± 0.01
    1 ± 0.01
    0.99 ± 0.01
        HDL-Cholesterol
    0.99 ± 0.01
    1.01 ± 0.01
    0.99 ± 0.01
    0.97 ± 0.01
        LDL-Cholesterol
    0.97 ± 0.01
    0.98 ± 0.01
    1.01 ± 0.01
    0.99 ± 0.01
        Triglycerides
    0.93 ± 0.01
    0.92 ± 0.01
    0.96 ± 0.01
    0.98 ± 0.01
    Statistical analysis title
    Analysis for total cholesterol
    Statistical analysis description
    Analysis for total cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0149
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.95
         upper limit
    1
    Statistical analysis title
    Analysis for total cholesterol
    Statistical analysis description
    Analysis for total cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.258
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.97
         upper limit
    1.01
    Statistical analysis title
    Analysis for HDL-cholesterol
    Statistical analysis description
    Analysis for HDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.8106
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    1.02
    Statistical analysis title
    Analysis for HDL cholesterol
    Statistical analysis description
    Analysis for HDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    1.06
    Statistical analysis title
    Analysis for LDL-cholesterol
    Statistical analysis description
    Analysis for LDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0185
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    0.99
    Statistical analysis title
    Analysis for LDL-cholesterol
    Statistical analysis description
    Analysis for LDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5996
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.96
         upper limit
    1.03
    Statistical analysis title
    Analysis for triglycerides
    Statistical analysis description
    Analysis for triglycerides was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1833
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    1.01
    Statistical analysis title
    Analysis for triglycerides
    Statistical analysis description
    Analysis for triglycerides was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0009
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    0.97

    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: lipid profile (free fatty acids)

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    End point title
    Change from baseline to last assessment in the trial in other treatment outcomes: lipid profile (free fatty acids)
    End point description
    Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (pulse rate).
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: mmol/L
        least squares mean (standard error)
    0.95 ± 0.02
    0.91 ± 0.01
    0.96 ± 0.02
    0.99 ± 0.02
    Statistical analysis title
    Analysis for free fatty acids
    Statistical analysis description
    Analysis for free fatty acids was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7796
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.95
         upper limit
    1.04
    Statistical analysis title
    Analysis for free fatty acids
    Statistical analysis description
    Analysis for free fatty acids was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    0.96

    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: urinary albumin to creatinine ratio

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    End point title
    Change from baseline to last assessment in the trial in other treatment outcomes: urinary albumin to creatinine ratio
    End point description
    Estimated ratio to baseline in urinary albumin to creatinine ratio at week 104 during the treatment period.
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: mg/g
        least squares mean (standard error)
    1.02 ± 0.05
    0.91 ± 0.05
    1.32 ± 0.07
    1.29 ± 0.06
    Statistical analysis title
    Analysis for urinary albumin to creatinine ratio
    Statistical analysis description
    Analysis for urinary albumin to creatinine ration was donne using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    0.89
    Statistical analysis title
    Analysis for urinary albumin to creatinine ratio
    Statistical analysis description
    Analysis for urinary albumin to creatinine ration was donne using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    0.81

    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: vital signs

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    End point title
    Change from baseline to last assessment in the trial in other treatment outcomes: vital signs
    End point description
    Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (diastolic blood pressure and systolic blood pressure).
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: mmHg
    least squares mean (standard error)
        Diastolic blood pressure (mmHg)
    -1.37 ± 0.32
    -1.57 ± 0.32
    -1.42 ± 0.32
    -1.71 ± 0.32
        Systolic blood pressure (mmHg)
    -3.44 ± 0.54
    -5.37 ± 0.54
    -2.17 ± 0.54
    -2.78 ± 0.54
    Statistical analysis title
    Analysis for diastolic blood pressure
    Statistical analysis description
    Analysis for diastolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9205
    Method
    Mixed models analysis
    Parameter type
    Treatment ratio
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.83
         upper limit
    0.92
    Statistical analysis title
    Analysis for diastolic blood pressure
    Statistical analysis description
    Analysis for diastolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7477
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.74
         upper limit
    1.03
    Statistical analysis title
    Analysis for systolic blood pressure
    Statistical analysis description
    Analysis for systolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0976
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -1.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.77
         upper limit
    0.23
    Statistical analysis title
    Analysis for systolic blood pressure
    Statistical analysis description
    Analysis for systolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0008
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -2.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.09
         upper limit
    -1.08

    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: vital signs (pulse rate)

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    End point title
    Change from baseline to last assessment in the trial in other treatment outcomes: vital signs (pulse rate)
    End point description
    Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (pulse rate).
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: beats/min
        least squares mean (standard error)
    2.12 ± 0.34
    2.41 ± 0.34
    0.09 ± 0.34
    -0.07 ± 0.34
    Statistical analysis title
    Analysis for pulse rate
    Statistical analysis description
    Analysis for pulse rate was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    2.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.07
         upper limit
    2.98
    Statistical analysis title
    Analysis for pulse rate
    Statistical analysis description
    Analysis for pulse rate was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    2.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.52
         upper limit
    3.43

    Secondary: Incidence during the trial in other treatment outcomes: hypoglycaemic events

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    End point title
    Incidence during the trial in other treatment outcomes: hypoglycaemic events
    End point description
    Rates (event rate per 100 exposure years) of severe or blood glucose confirmed symptomatic hypoglycaemia defned as an episode that was severe according to the ADA classification or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
    End point type
    Secondary
    End point timeframe
    Week 0 - 109
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: Event rate per 100 exposure years
        number (not applicable)
    37.5
    36.2
    35.3
    39.7
    No statistical analyses for this end point

    Secondary: Incidence during the trial in other treatment outcomes: adverse events

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    End point title
    Incidence during the trial in other treatment outcomes: adverse events
    End point description
    Rates (event rate per 100 years of exposure) of treatment emergent adverse events during the treatment period (weeks 0-109)
    End point type
    Secondary
    End point timeframe
    Weeks 0-109
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: Event rate per 100 years of exposure
        number (not applicable)
    330.5
    337
    317.4
    298.3
    No statistical analyses for this end point

    Secondary: Occurrence during the trial in other treatment outcomes: anti-semaglutide antibodies

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    End point title
    Occurrence during the trial in other treatment outcomes: anti-semaglutide antibodies [4]
    End point description
    The proportion of subjects that tested positive for anti-semaglutide antibodies at any time point post-baseline during the trial, from week 0 to week 109.
    End point type
    Secondary
    End point timeframe
    Weeks 0-109
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There will not be any antibody data for the two placebo arms. Thus the data is presented for only the 2 semaglutide arms for this endpoint.
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg
    Number of subjects analysed
    826
    822
    Units: proportion of subjects
        number (not applicable)
    1.4
    2.3
    No statistical analyses for this end point

    Secondary: Change from baseline to last assessment in the trial in other treatment outcomes: patient reported outcome (PRO)

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    End point title
    Change from baseline to last assessment in the trial in other treatment outcomes: patient reported outcome (PRO)
    End point description
    Estimated mean change from baseline to last assessment in the trial in patient reported outcomes (PRO). PRO questionnaire measured the individual overall health related quality of life namely bodily pain, general health, mental component summary, mental health, physical component summary, physical functioning, role-emotional, role-physical, social functioning and vitality. The PRO scores were transformed to a 0−100 scale with higher scores indicating greater health related quality of life.
    End point type
    Secondary
    End point timeframe
    Week 0, up to week 104
    End point values
    Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Number of subjects analysed
    826
    822
    824
    825
    Units: Score
    least squares mean (standard error)
        Bodily pain
    0.66 ± 0.35
    1.82 ± 0.35
    0.16 ± 0.35
    0.35 ± 0.35
        General health
    1.66 ± 0.29
    2.55 ± 0.29
    0.78 ± 0.29
    1.13 ± 0.3
        Mental component summary
    0 ± 0.35
    0.86 ± 0.35
    -0.17 ± 0.35
    -0.11 ± 0.35
        Mental health
    0.48 ± 0.33
    1.08 ± 0.33
    -0.14 ± 0.33
    -0.31 ± 0.33
        Physical component summary
    0.76 ± 0.28
    1.74 ± 0.28
    0.07 ± 0.28
    0.35 ± 0.28
        Physical functioning
    0.42 ± 0.32
    1.12 ± 0.32
    -0.38 ± 0.32
    -0.37 ± 0.33
        Role-emotional
    0.17 ± 0.42
    0.89 ± 0.42
    -0.36 ± 0.42
    -0.05 ± 0.42
        Role-physical
    0.39 ± 0.34
    1.18 ± 0.35
    -0.33 ± 0.35
    0.03 ± 0.35
        Social functioning
    -0.25 ± 0.35
    0.97 ± 0.35
    -0.2 ± 0.36
    -0.17 ± 0.36
        Vitality
    0.29 ± 0.31
    1.55 ± 0.31
    -0.04 ± 0.31
    0.35 ± 0.31
    Statistical analysis title
    Analysis for bodily pain
    Statistical analysis description
    Analysis for bodily pain was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.3171
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.48
         upper limit
    1.47
    Statistical analysis title
    Analysis for bodily pain
    Statistical analysis description
    Analysis for bodily pain was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0031
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    1.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.5
         upper limit
    2.45
    Statistical analysis title
    Analysis for general health
    Statistical analysis description
    Analysis for general health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.035
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    1.69
    Statistical analysis title
    Analysis for general health
    Statistical analysis description
    Analysis for general health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0007
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    1.42
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    2.24
    Statistical analysis title
    Analysis for mental component summary
    Statistical analysis description
    Analysis for mental component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7277
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.79
         upper limit
    1.13
    Statistical analysis title
    Analysis for mental component summary
    Statistical analysis description
    Analysis for mental component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0489
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1.94
    Statistical analysis title
    Analysis for mental health
    Statistical analysis description
    Analysis for mental health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.186
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    1.53
    Statistical analysis title
    Analysis for mental health
    Statistical analysis description
    Analysis for mental health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0029
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    2.31
    Statistical analysis title
    Analysis for physical component summary
    Statistical analysis description
    Analysis for physical component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0833
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.09
         upper limit
    1.45
    Statistical analysis title
    Analysis for physical component summary
    Statistical analysis description
    Analysis for physical component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0004
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    2.17
    Statistical analysis title
    Analysis for physical functioning
    Statistical analysis description
    Analysis for physical functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0799
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    1.69
    Statistical analysis title
    Analysis for physical functioning
    Statistical analysis description
    Analysis for physical functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0011
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    2.4
    Statistical analysis title
    Analysis for role emotional
    Statistical analysis description
    Analysis for role emotional was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1431
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.63
         upper limit
    1.68
    Statistical analysis title
    Analysis for role emotional
    Statistical analysis description
    Analysis for role emotional was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1136
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.22
         upper limit
    2.1
    Statistical analysis title
    Analysis for role physical
    Statistical analysis description
    Analysis for role physical was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1431
    Method
    Mixed models analysis
    Parameter type
    treatment difference
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.24
         upper limit
    1.67
    Statistical analysis title
    Analysis for role physical
    Statistical analysis description
    Analysis for role physical was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0197
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.18
         upper limit
    2.11
    Statistical analysis title
    Analysis for social fuctioning
    Statistical analysis description
    Analysis for social functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9223
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.03
         upper limit
    0.93
    Statistical analysis title
    Analysis for social functioning
    Statistical analysis description
    Analysis for social functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0237
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    1.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.15
         upper limit
    2.13
    Statistical analysis title
    Analysis for vitality
    Statistical analysis description
    Analysis for vitality was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 0.5 mg v Placebo 0.5 mg
    Number of subjects included in analysis
    1650
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4523
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.53
         upper limit
    1.19
    Statistical analysis title
    Analysis for vitality
    Statistical analysis description
    Analysis for vitality was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
    Comparison groups
    Semaglutide 1.0 mg v Placebo 1.0 mg
    Number of subjects included in analysis
    1647
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0064
    Method
    Mixed models analysis
    Parameter type
    Treatment difference
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    2.07

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events from the first trial-related activity after the subject had signed the informed consent (week -2) until the end of the posttreatment follow-up period (week 109).
    Adverse event reporting additional description
    Safety was assessed using the full analysis set which includes all randomised subjects. Subjects contribute to the evaluation as randomised.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Sema 0.5 mg
    Reporting group description
    -

    Reporting group title
    Sema 1.0 mg
    Reporting group description
    -

    Reporting group title
    Placebo 0.5 mg
    Reporting group description
    -

    Reporting group title
    Placebo 1.0 mg
    Reporting group description
    -

    Serious adverse events
    Sema 0.5 mg Sema 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    289 / 826 (34.99%)
    276 / 822 (33.58%)
    329 / 824 (39.93%)
    298 / 825 (36.12%)
         number of deaths (all causes)
    30
    32
    32
    28
         number of deaths resulting from adverse events
    3
    3
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    2 / 826 (0.24%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    2 / 824 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaplastic astrocytoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    B-cell lymphoma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-cell small lymphocytic lymphoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign lymph node neoplasm
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder papilloma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    2 / 824 (0.24%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma recurrent
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage II
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone cancer metastatic
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer in situ
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer stage III
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondroma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Choroid melanoma
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 826 (0.00%)
    4 / 822 (0.49%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial sarcoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extranodal marginal zone B-cell lymphoma (MALT type)
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder adenocarcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomus tumour
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Growth hormone-producing pituitary tumour
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic adenoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    2 / 822 (0.24%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip neoplasm malignant stage unspecified
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma stage 0
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma stage IV
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lung carcinoma cell type unspecified stage IV
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Neoplasm of appendix
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Pancreatic carcinoma stage IV
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraganglion neoplasm
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    2 / 824 (0.24%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phaeochromocytoma
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    3 / 826 (0.36%)
    3 / 822 (0.36%)
    4 / 824 (0.49%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage I
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage III
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer stage I
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 826 (0.00%)
    2 / 822 (0.24%)
    2 / 824 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer metastatic
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureteric cancer
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 826 (0.00%)
    2 / 822 (0.24%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 826 (0.12%)
    2 / 822 (0.24%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    2 / 826 (0.24%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial insufficiency
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral artery aneurysm
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral artery occlusion
         subjects affected / exposed
    1 / 826 (0.12%)
    2 / 822 (0.24%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    3 / 824 (0.36%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    3 / 826 (0.36%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    4 / 826 (0.48%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 826 (0.24%)
    0 / 822 (0.00%)
    3 / 824 (0.36%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leriche syndrome
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    2 / 826 (0.24%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    3 / 826 (0.36%)
    2 / 822 (0.24%)
    1 / 824 (0.12%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    2 / 824 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    2 / 824 (0.24%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abdominal hernia repair
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angioplasty
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brachytherapy
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid angioplasty
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stent insertion
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid endarterectomy
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    2 / 824 (0.24%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid revascularisation
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract operation
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary angioplasty
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    4 / 824 (0.49%)
    5 / 825 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary arterial stent insertion
         subjects affected / exposed
    15 / 826 (1.82%)
    8 / 822 (0.97%)
    17 / 824 (2.06%)
    17 / 825 (2.06%)
         occurrences causally related to treatment / all
    1 / 19
    1 / 9
    0 / 18
    2 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery bypass
         subjects affected / exposed
    8 / 826 (0.97%)
    5 / 822 (0.61%)
    14 / 824 (1.70%)
    10 / 825 (1.21%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
    1 / 14
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary revascularisation
         subjects affected / exposed
    11 / 826 (1.33%)
    10 / 822 (1.22%)
    15 / 824 (1.82%)
    9 / 825 (1.09%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 10
    1 / 17
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laparotomy
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical ventilation
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polypectomy
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Percutaneous coronary intervention
         subjects affected / exposed
    2 / 826 (0.24%)
    1 / 822 (0.12%)
    3 / 824 (0.36%)
    6 / 825 (0.73%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery angioplasty
         subjects affected / exposed
    2 / 826 (0.24%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery bypass
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stent insertion
         subjects affected / exposed
    1 / 826 (0.12%)
    3 / 822 (0.36%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral endarterectomy
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral revascularisation
         subjects affected / exposed
    2 / 826 (0.24%)
    4 / 822 (0.49%)
    5 / 824 (0.61%)
    9 / 825 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pterygium operation
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Removal of internal fixation
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal artery stent placement
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stent placement
         subjects affected / exposed
    2 / 826 (0.24%)
    2 / 822 (0.24%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon sheath incision
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia repair
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 826 (0.12%)
    3 / 822 (0.36%)
    5 / 824 (0.61%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 826 (0.24%)
    3 / 822 (0.36%)
    3 / 824 (0.36%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
    0 / 2
    Device malfunction
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia malignant
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metaplasia
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Microlithiasis
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Necrosis
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    8 / 826 (0.97%)
    5 / 822 (0.61%)
    8 / 824 (0.97%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 5
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    2 / 824 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    3 / 826 (0.36%)
    2 / 822 (0.24%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cyst
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymal tenderness
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erectile dysfunction
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital haemorrhage
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic obstruction
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Testicular cyst
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaginal prolapse
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acquired diaphragmatic eventration
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    3 / 826 (0.36%)
    2 / 822 (0.24%)
    0 / 824 (0.00%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 826 (0.36%)
    1 / 822 (0.12%)
    3 / 824 (0.36%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 826 (0.36%)
    5 / 822 (0.61%)
    7 / 824 (0.85%)
    7 / 825 (0.85%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 826 (0.73%)
    5 / 822 (0.61%)
    3 / 824 (0.36%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea at rest
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Lung cyst
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    2 / 824 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 826 (0.00%)
    2 / 822 (0.24%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 826 (0.24%)
    4 / 822 (0.49%)
    3 / 824 (0.36%)
    4 / 825 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pulmonary mass
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 826 (0.24%)
    1 / 822 (0.12%)
    2 / 824 (0.24%)
    5 / 825 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 826 (0.24%)
    3 / 822 (0.36%)
    3 / 824 (0.36%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 826 (0.00%)
    2 / 822 (0.24%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 826 (0.12%)
    2 / 822 (0.24%)
    3 / 824 (0.36%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Homicidal ideation
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    2 / 824 (0.24%)
    3 / 825 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic stress disorder
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizoaffective disorder
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep terror
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriogram coronary
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial test positive
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood glucose fluctuation
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheterisation cardiac
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulation time prolonged
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram ST segment abnormal
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram change
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic enzymes increased
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    1 / 824 (0.12%)
    2 / 825 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident at work
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia postoperative
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    2 / 826 (0.24%)
    0 / 822 (0.00%)
    2 / 824 (0.24%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burns third degree
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dural tear
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to anastomose
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    11 / 826 (1.33%)
    5 / 822 (0.61%)
    11 / 824 (1.33%)
    8 / 825 (0.97%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 5
    0 / 11
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 826 (0.12%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 826 (0.00%)
    0 / 822 (0.00%)
    0 / 824 (0.00%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 826 (0.12%)
    0 / 822 (0.00%)
    1 / 824 (0.12%)
    1 / 825 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 826 (0.00%)
    1 / 822 (0.12%)
    0 / 824 (0.00%)
    0 / 825 (0.00%)