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    Clinical Trial Results:
    A 52-week study comparing the efficacy and safety of once weekly IcoSema and once weekly insulin icodec, both treatment arms with or without oral anti-diabetic drugs, in participants with type 2 diabetes inadequately controlled with daily basal insulin. COMBINE 1

    Summary
    EudraCT number
    2020-005281-34
    Trial protocol
    FI   NO   BE   BG   PT   HR   IT  
    Global end of trial date
    23 Apr 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    09 May 2025
    First version publication date
    09 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1535-4591
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT05352815
    WHO universal trial number (UTN)
    U1111-1260-8259
    Other trial identifiers
    China Drug Trials (China): CTR20220768, Japan Registry for Clinical Trials (jRCT): jRCT2031220146
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Alle, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Office (2834), 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
    21 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm superiority of once weekly IcoSema compared with once weekly insulin icodec, both treatment arms with or without oral anti-diabetic drugs (OADs), in terms of glycaemic control measured by change in Haemoglobin A1c (HbA1c) from baseline after 52 weeks in subjects with type 2 diabetes (T2D) inadequately controlled with daily basal insulin.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki (64th WMA General Assembly, Fortaleza, Brazil. Oct 2013) and ICH Good Clinical Practice, including archiving of essential documents (Current step 4 version. 09 Nov 2016).
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    01 Jun 2022
    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
    Australia: 40
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Bulgaria: 59
    Country: Number of subjects enrolled
    China: 100
    Country: Number of subjects enrolled
    Finland: 27
    Country: Number of subjects enrolled
    Croatia: 46
    Country: Number of subjects enrolled
    India: 30
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Japan: 124
    Country: Number of subjects enrolled
    Korea, Republic of: 83
    Country: Number of subjects enrolled
    Mexico: 115
    Country: Number of subjects enrolled
    Norway: 15
    Country: Number of subjects enrolled
    Poland: 57
    Country: Number of subjects enrolled
    Portugal: 28
    Country: Number of subjects enrolled
    Romania: 47
    Country: Number of subjects enrolled
    Serbia: 31
    Country: Number of subjects enrolled
    Türkiye: 46
    Country: Number of subjects enrolled
    Taiwan: 30
    Country: Number of subjects enrolled
    United States: 295
    Country: Number of subjects enrolled
    South Africa: 81
    Worldwide total number of subjects
    1291
    EEA total number of subjects
    316
    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)
    784
    From 65 to 84 years
    507
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 192 sites in 20 countries.

    Pre-assignment
    Screening details
    Subjects with type 2 diabetes (T2D) inadequately controlled with daily basal insulin were randomised in 1:1 ratio to receive subcutaneous (s.c.) injection of IcoSema or insulin icodec once weekly with or without oral anti-diabetic drugs (OADs).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    IcoSema
    Arm description
    Subjects received once weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec and 2 milligrams per milliliter(mg/mL) of semaglutide for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    IcoSema
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Once-weekly subcutaneous injections of insulin icodec and semaglutide were administered for 52 weeks.

    Arm title
    Insulin Icodec
    Arm description
    Subjects received once weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec for 52 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Insulin Icodec
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Once-weekly subcutaneous injections of insulin icodec was administered for 52 weeks.

    Number of subjects in period 1
    IcoSema Insulin Icodec
    Started
    646
    645
    Full analysis set (FAS)
    646
    645
    Safety analysis set (SAS)
    644
    644
    Exposed
    644
    644
    Completed
    611
    611
    Not completed
    35
    34
         Adverse event, serious fatal
    2
    3
         Consent withdrawn by subject
    28
    24
         Lost to follow-up
    4
    7
         Site closure
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IcoSema
    Reporting group description
    Subjects received once weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec and 2 milligrams per milliliter(mg/mL) of semaglutide for 52 weeks.

    Reporting group title
    Insulin Icodec
    Reporting group description
    Subjects received once weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec for 52 weeks.

    Reporting group values
    IcoSema Insulin Icodec Total
    Number of subjects
    646 645 1291
    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)
    381 403 784
        From 65-84 years
    265 242 507
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.5 ( 10.5 ) 60.7 ( 10.2 ) -
    Gender Categorical
    Units: Participants
        Female
    246 246 492
        Male
    400 399 799
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    101 110 211
        Not Hispanic or Latino
    545 535 1080
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    5 1 6
        Asian
    216 204 420
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Black or African American
    19 25 44
        White
    404 410 814
        More than one race
    2 4 6
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    IcoSema
    Reporting group description
    Subjects received once weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec and 2 milligrams per milliliter(mg/mL) of semaglutide for 52 weeks.

    Reporting group title
    Insulin Icodec
    Reporting group description
    Subjects received once weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec for 52 weeks.

    Primary: Change in glycated haemoglobin (HbA1c)

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    End point title
    Change in glycated haemoglobin (HbA1c)
    End point description
    Change from baseline (week 0) to week 52 in HbA1c is presented. The outcome measure was evaluated based on the data from in study period, where all data from randomisation until last date of any of the following: 1) last direct subject-site contact; 2)subjects who withdrew their informed consent; 3) last subject-investigator contact as defined by the investigator for subjects who lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death of subjects who died before any of the above. Full Analysis Set (FAS) included all randomised subjects. Overall number of subjects analyzed = subjects with available data.
    End point type
    Primary
    End point timeframe
    From baseline week 0 (V2) to week 52 (V54)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    598
    605
    Units: Percentage point of HbA1c
        arithmetic mean (standard deviation)
    -1.60 ( 0.99 )
    -0.90 ( 1.01 )
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Change in HbA1c from baseline to week 52 is analysed using an analysis of covariance (ANCOVA) model with region and randomised treatment as fixed factors and baseline HbA1c as covariate. Missing HbA1c values at week 52 are imputed by using multiple imputation. Each imputed dataset is analysed separately and estimates are combined using Rubin's rules.
    Comparison groups
    IcoSema v Insulin Icodec
    Number of subjects included in analysis
    1203
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Treatment difference
    Point estimate
    -0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.76
         upper limit
    -0.57
    Notes
    [1] - Total number of subjects included in statistical analysis is 1291. The number given here is auto-calculated by the system.

    Secondary: Number of clinically significant hypoglycaemic episodes (level 2) (less than 3.0 millimoles per litre [mmol/L] (54 milligram per decilitre [mg/dL]), confirmed by blood glucose [BG] meter) or severe hypoglycaemic episodes (level 3)

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    End point title
    Number of clinically significant hypoglycaemic episodes (level 2) (less than 3.0 millimoles per litre [mmol/L] (54 milligram per decilitre [mg/dL]), confirmed by blood glucose [BG] meter) or severe hypoglycaemic episodes (level 3)
    End point description
    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 2 was less than (<) 3.0 mmol/L (54 mg/dL) and level 3 had no specific glucose threshold. The outcome measure was evaluated based on data from on treatment period, where all data from date of first dose of randomised treatment as recorded on the electronic case report form (eCRF) until the first date of any of the following: 1) last follow-up visit ; 2) last date on randomised treatment +6 weeks (corresponding to 5 weeks after the end of the dosing interval for both treatment arms); 3) end date for the in-study data points sets. Safety analysis set (SAS) included all randomised subjects who are exposed to randomised treatment.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 57 (V56)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    644
    644
    Units: Episodes
        number (not applicable)
    91
    424
    No statistical analyses for this end point

    Secondary: Time in range 3.9-10.0 mmol/L (70-180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6

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    End point title
    Time in range 3.9-10.0 mmol/L (70-180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6
    End point description
    Time in range was defined as 100 times the number of recorded measurements in glycemic range 3.9-10.0 mmol/L (70-180 mg/dL), both inclusive, divided by the total number of recorded measurements. The outcome measure was evaluated based on the data from in study period: Data from randomisation until last date of any of the following: 1) the last direct subject-site contact; 2) withdrawal for subjects who withdraw their informed consent; 3) the last subject-investigator contact as defined by the investigator for subjects who are lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death for subjects who die before any of the above. FAS included all randomised subjects. Overall number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From week 48 (V50) to week 52 (V54)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    481
    488
    Units: Percentage of time
        arithmetic mean (standard deviation)
    75.9 ( 16.1 )
    61.9 ( 18.1 )
    No statistical analyses for this end point

    Secondary: Change in body weight

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    End point title
    Change in body weight
    End point description
    Change from baseline (week 0) to week 52 in body weight is presented. The outcome measure was evaluated based on the data from in study period, where all data from randomisation until last date of any of the following: 1) last direct subject-site contact; 2) subjects who withdrew their informed consent; 3) last subject-investigator contact as defined by the investigator for subjects who lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death of subjects who died before any of the above. FAS included all randomised subjects. Overall number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 52 (V54)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    606
    610
    Units: Kilogram (Kg)
        arithmetic mean (standard deviation)
    -3.71 ( 4.87 )
    1.96 ( 4.76 )
    No statistical analyses for this end point

    Secondary: Time spent less than 3.0 mmol/L (54 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6

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    End point title
    Time spent less than 3.0 mmol/L (54 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6
    End point description
    Time spent below threshold was defined as 100 times the number of recorded measurements below the threshold, divided by the total number of recorded measurements. The outcome measure was evaluated based on the data from in study period: Data from randomisation until last date of any of the following: 1) the last direct subject-site contact; 2) withdrawal for subjects who withdraw their informed consent; 3) the last subject-investigator contact as defined by the investigator for subjects who are lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death for subjects who die before any of the above. FAS included all randomised subjects. Overall number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From week 48 (V50) to week 52 (V54)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    481
    488
    Units: Percentage of time
        arithmetic mean (standard deviation)
    0.27 ( 0.55 )
    0.33 ( 0.82 )
    No statistical analyses for this end point

    Secondary: Time spent more than 10.0 mmol/L (180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6

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    End point title
    Time spent more than 10.0 mmol/L (180 mg/dL) using continuous glucose monitoring (CGM) system, Dexcom G6
    End point description
    Time spent above threshold is defined as 100 times the number of recorded measurements above the threshold, divided by the total number of recorded measurements. The outcome measure was evaluated based on the data from in study period: Data from randomisation until last date of any of the following: 1) the last direct subject-site contact; 2) withdrawal for subjects who withdraw their informed consent; 3) the last subject-investigator contact as defined by the investigator for subjects who are lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death for subjects who die before any of the above. FAS included all randomised subjects. Overall number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From week 48 (V50) to week 52 (V54)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    481
    488
    Units: Percentage of time
        arithmetic mean (standard deviation)
    23.2 ( 16.3 )
    36.7 ( 18.7 )
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose (FPG)

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    End point title
    Change in fasting plasma glucose (FPG)
    End point description
    Change in FPG from baseline (week 0) to week 52 is presented. The outcome measure was evaluated based on the data from in study period: Data from randomisation until last date of any of the following: 1) the last direct subject-site contact; 2) withdrawal for subjects who withdraw their informed consent; 3) the last subject-investigator contact as defined by the investigator for subjects who are lost to follow-up (i.e. possibly an unscheduled phone visit); 4) death for subjects who die before any of the above. FAS included all randomised subjects. Overall number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 52 (V54)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    552
    572
    Units: Millimoles per litre (mmol/L)
        arithmetic mean (standard deviation)
    -1.90 ( 3.01 )
    -1.65 ( 2.96 )
    No statistical analyses for this end point

    Secondary: Weekly basal insulin dose

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    End point title
    Weekly basal insulin dose
    End point description
    Estimated mean average weekly basal insulin dose from week 50 to week 52 of treatment is presented. The outcome measure was evaluated based on data from on treatment period, where all data from date of first dose of randomised treatment as recorded on the electronic case report form (eCRF) until the first date of any of the following: 1) last follow-up visit (V56); 2) last date on randomised treatment +6 weeks (corresponding to 5 weeks after the end of the dosing interval for both treatment arms); 3) end-date for the in-study data points sets. SAS included all randomised subjects who are exposed to randomised treatment. Overall number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From week 50 (V52) to week 52 (V54)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    575
    596
    Units: Units of insulin
        arithmetic mean (standard deviation)
    170.6 ( 83.3 )
    366.5 ( 225.5 )
    No statistical analyses for this end point

    Secondary: Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter)

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    End point title
    Number of clinically significant hypoglycaemic episodes (level 2) (<3.0 mmol/L (54 mg/dL), confirmed by BG meter)
    End point description
    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 2 was less than (<) 3.0 mmol/L (54 mg/dL). The outcome measure was evaluated based on data from on treatment period, where all data from date of first dose of randomised treatment as recorded on the electronic case report form (eCRF) until the first date of any of the following: 1) last follow-up visit ; 2) last date on randomised treatment +6 weeks (corresponding to 5 weeks after the end of the dosing interval for both treatment arms); 3) end-date for the in-study data points sets. SAS included all randomised subjects who are exposed to randomised treatment. Overall number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 57 (V56)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    644
    644
    Units: Episodes
        number (not applicable)
    90
    419
    No statistical analyses for this end point

    Secondary: Number of severe hypoglycaemic episodes (level 3)

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    End point title
    Number of severe hypoglycaemic episodes (level 3)
    End point description
    Hypoglycaemic episodes were classified according to the American Diabetes Association/ International Hypoglycaemia Study Group, where glycemic criteria for level 3 had no specific glucose threshold. The outcome measure was evaluated based on data from on treatment period, where all data from date of first dose of randomised treatment as recorded on the electronic case report form (eCRF) until the first date of any of the following: 1) last follow-up visit; 2) last date on randomised treatment +6 weeks(corresponding to 5 weeks after the end of the dosing interval for both treatment arms); 3) end-date for the in-study data points sets. SAS included all randomised subjects who are exposed to randomised treatment. Overall number of subjects analyzed = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline week 0 (V2) to week 57 (V56)
    End point values
    IcoSema Insulin Icodec
    Number of subjects analysed
    644
    644
    Units: Episodes
        number (not applicable)
    1
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 0 to week 57
    Adverse event reporting additional description
    Presented AEs are TEAEs, defined as event with onset during on treatment period where all data from date of first dose of randomised treatment as recorded on electronic case report form until first date of any of the below: last follow up visit; last date on randomised treatment +6 weeks; end-date for in-study data points.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Insulin Icodec
    Reporting group description
    Subjects received once weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec for 52 weeks.

    Reporting group title
    IcoSema
    Reporting group description
    Subjects received once weekly subcutaneous injections of 700 units per milliliter (U/mL) of insulin icodec and 2 milligrams per milliliter(mg/mL) of semaglutide for 52 weeks.

    Serious adverse events
    Insulin Icodec IcoSema
    Total subjects affected by serious adverse events
         subjects affected / exposed
    69 / 644 (10.71%)
    59 / 644 (9.16%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    2 / 644 (0.31%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (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 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         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 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (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
    2 / 644 (0.31%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (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
    Breast haematoma
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 644 (0.31%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 644 (0.47%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Adjustment disorder with depressed mood
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cartilage injury
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip injury
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    2 / 644 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth fracture
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    5 / 644 (0.78%)
    2 / 644 (0.31%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 644 (0.31%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 644 (0.31%)
    2 / 644 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Degenerative aortic valve disease
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    3 / 644 (0.47%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    4 / 644 (0.62%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 644 (0.31%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 644 (0.31%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    2 / 644 (0.31%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 644 (0.16%)
    2 / 644 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine with aura
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         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
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular oedema
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         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 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 644 (0.31%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gastroparesis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 644 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 644 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotid gland enlargement
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Terminal ileitis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 644 (0.31%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 644 (0.31%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (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
    Acute kidney injury
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (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 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postrenal failure
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 644 (0.00%)
    2 / 644 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthropathy
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (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 limb
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 644 (0.16%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 644 (0.16%)
    3 / 644 (0.47%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (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 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 644 (0.62%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (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 / 644 (0.16%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 644 (0.16%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 644 (0.00%)
    1 / 644 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    3 / 644 (0.47%)
    0 / 644 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Insulin Icodec IcoSema
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    258 / 644 (40.06%)
    354 / 644 (54.97%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 644 (2.95%)
    37 / 644 (5.75%)
         occurrences all number
    27
    41
    Headache
         subjects affected / exposed
    20 / 644 (3.11%)
    33 / 644 (5.12%)
         occurrences all number
    26
    58
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    35 / 644 (5.43%)
    41 / 644 (6.37%)
         occurrences all number
    41
    46
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    8 / 644 (1.24%)
    39 / 644 (6.06%)
         occurrences all number
    8
    55
    Diarrhoea
         subjects affected / exposed
    46 / 644 (7.14%)
    102 / 644 (15.84%)
         occurrences all number
    65
    187
    Nausea
         subjects affected / exposed
    24 / 644 (3.73%)
    153 / 644 (23.76%)
         occurrences all number
    29
    348
    Dyspepsia
         subjects affected / exposed
    10 / 644 (1.55%)
    44 / 644 (6.83%)
         occurrences all number
    11
    64
    Vomiting
         subjects affected / exposed
    17 / 644 (2.64%)
    68 / 644 (10.56%)
         occurrences all number
    19
    118
    Infections and infestations
    COVID-19
         subjects affected / exposed
    61 / 644 (9.47%)
    67 / 644 (10.40%)
         occurrences all number
    62
    68
    Nasopharyngitis
         subjects affected / exposed
    51 / 644 (7.92%)
    38 / 644 (5.90%)
         occurrences all number
    62
    50
    Upper respiratory tract infection
         subjects affected / exposed
    69 / 644 (10.71%)
    54 / 644 (8.39%)
         occurrences all number
    84
    64
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 644 (0.16%)
    38 / 644 (5.90%)
         occurrences all number
    1
    48

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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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