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    Clinical Trial Results:
    Effect of semaglutide once-weekly versus insulin aspart three times daily, both as add on to metformin and optimised insulin glargine (U100) in subjects with type 2 diabetes A 52-week, multi-centre, multinational, open-label, activecontrolled, two armed, parallel-group, randomised trial in subjects with type 2 diabetes

    Summary
    EudraCT number
    		 2017-003219-20
    Trial protocol
    		 SK   SI   EE   BG   LV   PL   GR   DE   CZ   LT   PT   ES   HR   HU   RO  
    Global end of trial date
    22 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Mar 2022
    First version publication date
    10 Mar 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NN9535-4386
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03689374
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Alle, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Office (2843), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Office (2834), 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
    01 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of once-weekly semaglutide subcutaneously (s.c.) on glycaemic control versus insulin aspart three times daily, both as add on to metformin and optimised insulin glargine (U100) in subjects with type 2 diabetes (T2D).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and International Council for Harmonisation (ICH) Good Clinical Practice (2016), including archiving of essential documents, EN ISO 14155 and 21 US Code of Federal Regulations (CFR) 312.120.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 123
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 51
    Country: Number of subjects enrolled
    Czechia: 51
    Country: Number of subjects enrolled
    Germany: 223
    Country: Number of subjects enrolled
    Spain: 82
    Country: Number of subjects enrolled
    Estonia: 34
    Country: Number of subjects enrolled
    Greece: 129
    Country: Number of subjects enrolled
    Croatia: 58
    Country: Number of subjects enrolled
    Hungary: 78
    Country: Number of subjects enrolled
    India: 346
    Country: Number of subjects enrolled
    Lithuania: 40
    Country: Number of subjects enrolled
    Latvia: 73
    Country: Number of subjects enrolled
    North Macedonia: 45
    Country: Number of subjects enrolled
    Poland: 271
    Country: Number of subjects enrolled
    Portugal: 22
    Country: Number of subjects enrolled
    Romania: 70
    Country: Number of subjects enrolled
    Serbia: 223
    Country: Number of subjects enrolled
    Slovakia: 89
    Country: Number of subjects enrolled
    Slovenia: 35
    Country: Number of subjects enrolled
    Turkey: 103
    Country: Number of subjects enrolled
    South Africa: 128
    Worldwide total number of subjects
    2274
    EEA total number of subjects
    1378
    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)
    1422
    From 65 to 84 years
    849
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Trial conducted at 209 sites (21 countries): Bosnia-Herzegovina (3), Bulgaria (9), Croatia (7), Czech Republic (7), Estonia (5), Germany (25), Greece (14), Hungary (8), India (20), Latvia (7), Lithuania (6), Macedonia (3), Poland (20), Portugal (6), Romania (7), Serbia (14), Slovakia (9), Slovenia (6), South Africa (11), Spain (8) and Turkey (14).

    Pre-assignment
    Screening details
    		 This trial consisted of 12-week run-in, 52-week treatment period and subjects were followed up 5 weeks for safety. Subjects were randomised 1:1 to receive treatment with: metformin + insulin glargine (IGlar) U100 + once-weekly semaglutide subcutaneously (s.c). or metformin + insulin glargine U100 + mealtime insulin aspart s.c. three times daily.

    Period 1
    Period 1 title
    Run-in period (12 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All subjects
    Arm description
    		 During run-in period insulin glargine in combination with metformin was to be optimised. All enrolled subjects received metformin orally and IGlar U100 s.c. injection in run-in period. Metformin was optimised in dose range of greater than or equal to (>=) 1500 milligrams (mg) to less than or equal to (<=) 3000 mg. After run-in period, subjects were randomised 1:1 to receive add-on treatment with semaglutide once weekly or insulin aspart three times daily (TID) in treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    subjects received IGlar U100 s.c. injection.

    Number of subjects in period 1
    		All subjects
    Started
    2274
    Completed
    1748
    Not completed
    526
         Run-in failure
    526
    Period 2
    Period 2 title
    Treatment Period (Week 0 to 52)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Semaglutide
    Arm description
    		 Subjects received metformin, IGlar U100 and semaglutide up to week 52. Metformin dose was maintained at same level and frequency as optimised in run-in period unless safety concern related to background medication arose; IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast self-measured plasma glucose (SMPG) values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia. Subjects self-administered s.c. injection of semaglutide at an initiation dose of 0.25 mg once weekly, after 4 weeks dose was increased to 0.5 mg, and 1 mg after at least 4 weeks to further improve glycaemic control, at investigator’s discretion. Dose reduction from 1 to 0.5 mg was allowed in case of safety concern/unacceptable intolerability. Subjects were followed up for 5 weeks (week 57) for safety.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Lantus®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast SMPG values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia.

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Ozempic®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects self-administered s.c. injection of semaglutide at an initiation dose of 0.25 mg once weekly, after 4 weeks dose was increased to 0.5 mg, and 1 mg after at least 4 weeks to further improve glycaemic control, at investigator’s discretion. Dose reduction from 1 to 0.5 mg was allowed in case of safety concern/unacceptable intolerability.

    Arm title
    		 Insulin Aspart
    Arm description
    		 Subjects received metformin, IGlar U100 and insulin aspart up to week 52. Metformin dose was maintained at same level and frequency as optimised in run-in period unless safety concern related to background medication arose; IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast SMPG values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia. Subjects self-administered s.c. injection of insulin aspart at an initiation dose of 4 units three times daily, dose adjustments were considered twice weekly based on pre-prandial and bedtime SMPG from the preceding 3 days and the individualised goal according to investigator’s discretion. Subjects were followed up for 5 weeks (week 57) for safety.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    NovoRapid®/NovoLog®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects self-administered s.c. injection of insulin aspart at an initiation dose of 4 units three times daily, dose adjustments were considered twice weekly based on pre-prandial and bedtime SMPG from the preceding 3 days and the individualised goal according to investigator’s discretion.

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Lantus®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast SMPG values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline data was collected only for randomised subject in treatment period.
    Number of subjects in period 2 [2]
    		Semaglutide Insulin Aspart
    Started
    874
    874
    Completed
    850
    831
    Not completed
    24
    43
         Consent withdrawn by subject
    10
    38
         Death
    11
    1
         Lost to follow-up
    3
    4
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Period 1 was run-in period, baseline data was collected only for subjects randomised in treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide
    Reporting group description
    		 Subjects received metformin, IGlar U100 and semaglutide up to week 52. Metformin dose was maintained at same level and frequency as optimised in run-in period unless safety concern related to background medication arose; IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast self-measured plasma glucose (SMPG) values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia. Subjects self-administered s.c. injection of semaglutide at an initiation dose of 0.25 mg once weekly, after 4 weeks dose was increased to 0.5 mg, and 1 mg after at least 4 weeks to further improve glycaemic control, at investigator’s discretion. Dose reduction from 1 to 0.5 mg was allowed in case of safety concern/unacceptable intolerability. Subjects were followed up for 5 weeks (week 57) for safety.

    Reporting group title
    Insulin Aspart
    Reporting group description
    		 Subjects received metformin, IGlar U100 and insulin aspart up to week 52. Metformin dose was maintained at same level and frequency as optimised in run-in period unless safety concern related to background medication arose; IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast SMPG values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia. Subjects self-administered s.c. injection of insulin aspart at an initiation dose of 4 units three times daily, dose adjustments were considered twice weekly based on pre-prandial and bedtime SMPG from the preceding 3 days and the individualised goal according to investigator’s discretion. Subjects were followed up for 5 weeks (week 57) for safety.

    Reporting group values
    		 Semaglutide Insulin Aspart Total
    Number of subjects
    		 874 874 1748
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 575 530 1105
        From 65-84 years
    		 299 343 642
        85 years and over
    		 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.8 ± 9.4 61.5 ± 9.5 -
    Gender Categorical
    Units: Subjects
        Female
    		 429 425 854
        Male
    		 445 449 894

    End points

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    End points reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 During run-in period insulin glargine in combination with metformin was to be optimised. All enrolled subjects received metformin orally and IGlar U100 s.c. injection in run-in period. Metformin was optimised in dose range of greater than or equal to (>=) 1500 milligrams (mg) to less than or equal to (<=) 3000 mg. After run-in period, subjects were randomised 1:1 to receive add-on treatment with semaglutide once weekly or insulin aspart three times daily (TID) in treatment period.
    Reporting group title
    Semaglutide
    Reporting group description
    		 Subjects received metformin, IGlar U100 and semaglutide up to week 52. Metformin dose was maintained at same level and frequency as optimised in run-in period unless safety concern related to background medication arose; IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast self-measured plasma glucose (SMPG) values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia. Subjects self-administered s.c. injection of semaglutide at an initiation dose of 0.25 mg once weekly, after 4 weeks dose was increased to 0.5 mg, and 1 mg after at least 4 weeks to further improve glycaemic control, at investigator’s discretion. Dose reduction from 1 to 0.5 mg was allowed in case of safety concern/unacceptable intolerability. Subjects were followed up for 5 weeks (week 57) for safety.

    Reporting group title
    Insulin Aspart
    Reporting group description
    		 Subjects received metformin, IGlar U100 and insulin aspart up to week 52. Metformin dose was maintained at same level and frequency as optimised in run-in period unless safety concern related to background medication arose; IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast SMPG values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia. Subjects self-administered s.c. injection of insulin aspart at an initiation dose of 4 units three times daily, dose adjustments were considered twice weekly based on pre-prandial and bedtime SMPG from the preceding 3 days and the individualised goal according to investigator’s discretion. Subjects were followed up for 5 weeks (week 57) for safety.

    Primary: Change in HbA1c (%-point)

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    End point title
    		 Change in HbA1c (%-point)
    End point description
    Change from baseline in HbA1c (measured in %) at week 52 is presented. Data is reported for ‘on-treatment’ observation period: from the date of first dose of trial product (week 0) to the last date on trial product with a visit window of +7 days (week 52). Full analysis set included all randomised subjects. Number of Subjects Anlaysed = subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline (week 0), week 52
    End point values
    		 Semaglutide Insulin Aspart
    Number of subjects analysed
    795
    783
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -1.5 ± 1.0
    -1.2 ± 1.0
    Statistical analysis title
    		 Semaglutide versus insulin aspart
    Statistical analysis description
    The responses were analysed using an ANCOVA with treatment as fixed factor and baseline value as a covariate. Before analysis, missing data were multiple imputed using observed data from subjects within the same group defined by randomised treatment, using a regression model including randomised treatment group and data from baseline and all previous visits as covariates. The prespecified non inferiority margin was 0.3%-point.
    Comparison groups
    Semaglutide v Insulin Aspart
    Number of subjects included in analysis
    1578
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001 [1]
    Method
    		 t-distributed test
    Parameter type
    		 Treatment difference
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 -0.2
    Notes
    [1] - The non-inferiority p-value was calculated as two times the one-sided p-value from a t-distributed test.

    Secondary: Time to first event adjudication committee confirmed severe hypoglycaemic episode (American Diabetes Association)

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    End point title
    		 Time to first event adjudication committee confirmed severe hypoglycaemic episode (American Diabetes Association)
    End point description
    Rates per 100 years of exposure time for first EAC confirmed severe hypoglycaemic episodes from randomization (week 0) to week 52 are presented. As per 2013 ADA criteria severe hypoglycaemic episodes were episodes with plasma glucose (PG) less than or equal to (<=) 3.9 millimoles per liter (mmol/L) (70 milligrams per deciliter (mg/dL)). EAC confirmed-severe hypoglycaemia was an episode requiring assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. Data is reported for ‘on-treatment’ observation period: from the date of first dose of trial product (week 0) to the last date on trial product with a visit window of +7 days (week 52). Full analysis set included all randomised subjects. Number of Subjects Anlaysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    From randomization (week 0) to week 52
    End point values
    		 Semaglutide Insulin Aspart
    Number of subjects analysed
    874
    864
    Units: Rate per 100 years of exposure
        number (not applicable)
    0.42
    0.73
    No statistical analyses for this end point

    Secondary: Time to first event adjudication committee confirmed severe hypoglycaemic episode (American Diabetes Association) requiring hospitalisation, documented medical help, or is life threatening

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    End point title
    		 Time to first event adjudication committee confirmed severe hypoglycaemic episode (American Diabetes Association) requiring hospitalisation, documented medical help, or is life threatening
    End point description
    Rates per 100 years of exposure time for first EAC confirmed severe hypoglycaemic episodes requiring hospitalization, documented medical help, or is life threatening from randomization (week 0) to week 52 are presented. As per 2013 ADA criteria severe hypoglycaemic episodes were episodes with PG <= 3.9 mmol/L (70 mg/dL). EAC confirmed-severe hypoglycaemia was an episode requiring assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. Data is reported for ‘on-treatment’ observation period: from the date of first dose of trial product (week 0) to the last date on trial product with a visit window of +7 days (week 52). Full analysis set included all randomised subjects. Number of Subjects Analysed = subjects with available data for this endpoint
    End point type
    Secondary
    End point timeframe
    From randomization (week 0) to week 52
    End point values
    		 Semaglutide Insulin Aspart
    Number of subjects analysed
    874
    864
    Units: Rate per 100 years of exposure
        number (not applicable)
    0.21
    0.44
    No statistical analyses for this end point

    Secondary: Change in body weight (kilograms (kg))

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    End point title
    		 Change in body weight (kilograms (kg))
    End point description
    Change from baseline in body weight (measured in kg) at week 52 is presented. Data is reported for ‘on-treatment’ observation period: from the date of first dose of trial product (week 0) to the last date on trial product with a visit window of +7 days (week 52). Full analysis set included all randomised subjects. Number of Subjects Analyzed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (week 0), week 52
    End point values
    		 Semaglutide Insulin Aspart
    Number of subjects analysed
    801
    793
    Units: kilograms
        arithmetic mean (standard deviation)
    -4.2 ± 4.6
    2.9 ± 4.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From week 0 to week 52
    Adverse event reporting additional description
    All presented adverse events (AEs) are treatment-emergent (i.e., TEAEs). TEAEs were defined as AEs with onset during the ‘on-treatment’ observation period. Results are based on the safety analysis set (SAS) which included all subjects exposed to at least one dose of trial product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Insulin Aspart
    Reporting group description
    		 Subjects received metformin, IGlar U100 and insulin aspart for 52 weeks in treatment period. Metformin dose was maintained at same level and frequency as optimized in run-in period unless safety concern related to background medication arose; IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast SMPG values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia. Subjects self-administered s.c. injection of insulin aspart at an initiation dose of 4 units three times daily, dose adjustments were considered twice weekly based on pre-prandial and bedtime SMPG from the preceding 3 days and the individualized goal according to investigator’s discretion. Subjects were followed up for 5 weeks (week 57) for safety.

    Reporting group title
    Semaglutide
    Reporting group description
    		 Subjects received metformin, IGlar U100 and semaglutide for 52 weeks in treatment period. Metformin dose was maintained at same level and frequency as optimized in run-in period unless safety concern related to background medication arose; IGlar U100 dose was adjusted in run-in period, increases in IGlar U100 dose was based on mean of 3 prebreakfast self-measured plasma glucose (SMPG) values obtained on day of visit/telephone contact and 2 days before contact and dose reduction of IGlar U100 was considered in accordance with approved local label to reduce risk of hypoglycaemia. Subjects self-administered s.c. injection of semaglutide at an initiation dose of 0.25 mg once weekly, after 4 weeks dose was increased to 0.5 mg, and 1 mg after at least 4 weeks to further improve glycaemic control, at investigator’s discretion. Dose reduction from 1 to 0.5 mg was allowed in case of safety concern/unacceptable intolerability. Subjects were followed up for 5 weeks (week 57) for safety.

    Serious adverse events
    		 Insulin Aspart Semaglutide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    84 / 864 (9.72%)
    65 / 874 (7.44%)
         number of deaths (all causes)
    1
    12
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammatory pseudotumour
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal papilloma of breast
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to gastrointestinal tract
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal squamous cell carcinoma
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ovarian cancer
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal neoplasm
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma recurrent
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cancer
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hernia repair
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Removal of internal fixation
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Therapeutic procedure
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toe amputation
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adhesion
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Impaired healing
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular stent stenosis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Electric shock
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fall
         subjects affected / exposed
    2 / 864 (0.23%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrong product administered
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    4 / 864 (0.46%)
    3 / 874 (0.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    2 / 864 (0.23%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    2 / 864 (0.23%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 864 (0.35%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 864 (0.12%)
    2 / 874 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 864 (0.12%)
    4 / 874 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    3 / 864 (0.35%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    4 / 864 (0.46%)
    2 / 874 (0.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 864 (0.35%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic ischaemic neuropathy
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal polyp
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 864 (0.23%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice cholestatic
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder perforation
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 864 (0.00%)
    3 / 874 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Facet joint syndrome
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess sweat gland
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 864 (0.23%)
    3 / 874 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Diabetic gangrene
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gangrene
         subjects affected / exposed
    0 / 864 (0.00%)
    3 / 874 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 864 (0.58%)
    3 / 874 (0.34%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 864 (0.00%)
    2 / 874 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 864 (0.23%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal abscess
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 864 (0.12%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 864 (0.23%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia unawareness
         subjects affected / exposed
    1 / 864 (0.12%)
    0 / 874 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 864 (0.00%)
    1 / 874 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Insulin Aspart Semaglutide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 864 (7.52%)
    225 / 874 (25.74%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    22 / 864 (2.55%)
    65 / 874 (7.44%)
         occurrences all number
    29
    98
    Nausea
         subjects affected / exposed
    7 / 864 (0.81%)
    129 / 874 (14.76%)
         occurrences all number
    7
    174
    Vomiting
         subjects affected / exposed
    5 / 864 (0.58%)
    50 / 874 (5.72%)
         occurrences all number
    6
    78
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    51 / 864 (5.90%)
    57 / 874 (6.52%)
         occurrences all number
    73
    69

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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