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    Clinical Trial Results:
    Efficacy and long-term safety of oral semaglutide versus sitagliptin in subjects with type 2 diabetes

    Summary
    EudraCT number
    2015-001351-71
    Trial protocol
    DE   GB  
    Global end of trial date
    28 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Apr 2019
    First version publication date
    12 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9924-4222
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02607865
    WHO universal trial number (UTN)
    U1111-1168-4339
    Other trial identifiers
    JapicCTI: 163174
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of once-daily dosing of three dose levels (3 mg, 7 mg and 14 mg) of oral semaglutide versus sitagliptin 100 mg once-daily, both in combination with metformin with or without sulfonylurea (SU), on glycaemic control in subjects with type 2 diabetes mellitus (T2DM).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013), ICH Good Clinical Practice, including archiving of essential documents (1996), and 21 CFR 312.120.
    Background therapy
    Subjects were to continue their pre-trial metformin (≥1500 mg or maximum tolerated dose) alone or in combination with sulphonylurea (SU) (≥half of the maximum approved dose according to local label or maximum tolerated dose) throughout the trial.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    15 Feb 2016
    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
    Argentina: 104
    Country: Number of subjects enrolled
    Brazil: 23
    Country: Number of subjects enrolled
    Germany: 105
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    United Kingdom: 118
    Country: Number of subjects enrolled
    Israel: 65
    Country: Number of subjects enrolled
    Japan: 207
    Country: Number of subjects enrolled
    Mexico: 109
    Country: Number of subjects enrolled
    Romania: 142
    Country: Number of subjects enrolled
    Russian Federation: 106
    Country: Number of subjects enrolled
    Turkey: 66
    Country: Number of subjects enrolled
    Ukraine: 100
    Country: Number of subjects enrolled
    United States: 538
    Country: Number of subjects enrolled
    South Africa: 144
    Worldwide total number of subjects
    1863
    EEA total number of subjects
    401
    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)
    1362
    From 65 to 84 years
    501
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 200 sites in 14 countries: Argentina-5, Brazil-1, France-10, Germany-12, Israel-8, Japan-16, Mexico-5, Romania-12, Russian Federation-8, South Africa-11, Turkey-7, Ukraine-8, United Kingdom (UK)-14, United States (US)-83. In addition, 6 sites screened, but didn’t randomise any subjects: France-1, Turkey-1, UK-1 and US-3.

    Pre-assignment
    Screening details
    Not applicable.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The trial was double-blinded and the clinical study group and the investigator remained blinded throughout the trial. The blinding was to be maintained until the database had been released for statistical analysis after database lock. For both semaglutide and sitagliptin, respectively, the active trial product and the corresponding placebo tablets were visually identical.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Oral semaglutide 3 mg
    Arm description
    Subjects were to take oral semaglutide 3 mg tablets once daily from weeks 1 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.
    Arm type
    Experimental

    Investigational medicinal product name
    Semaglutide 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Semaglutide tablets were to be taken once daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The trial product could be taken with up to half a glass of water (approximately 120 mL/4 fluid oz) and was to be swallowed whole and not broken or chewed. Oral medication other than trial product could only be taken 30 minutes after administration of trial product.

    Investigational medicinal product name
    Sitagliptin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin placebo tablets were to be taken once daily throughout the trial. The sitagliptin tablet was to be swallowed whole and not broken or chewed and could be taken with or without food.

    Arm title
    Oral semaglutide 7 mg
    Arm description
    Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from weeks 1 - 78: 3 mg from weeks 1 - 4 and 7 mg from weeks 5 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.
    Arm type
    Experimental

    Investigational medicinal product name
    Semaglutide 7 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Semaglutide tablets were to be taken once daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The trial product could be taken with up to half a glass of water (approximately 120 mL/4 fluid oz) and was to be swallowed whole and not broken or chewed. Oral medication other than trial product could only be taken 30 minutes after administration of trial product.

    Investigational medicinal product name
    Sitagliptin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin placebo tablets were to be taken once daily throughout the trial. The sitagliptin tablet was to be swallowed whole and not broken or chewed and could be taken with or without food.

    Arm title
    Oral semaglutide 14 mg
    Arm description
    Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from weeks 1 - 78: 3 mg from weeks 1 - 4, 7 mg from weeks 5 - 8 and 14 mg from weeks 9 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.
    Arm type
    Experimental

    Investigational medicinal product name
    Semaglutide 14 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Semaglutide tablets were to be taken once daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The trial product could be taken with up to half a glass of water (approximately 120 mL/4 fluid oz) and was to be swallowed whole and not broken or chewed. Oral medication other than trial product could only be taken 30 minutes after administration of trial product.

    Investigational medicinal product name
    Sitagliptin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin placebo tablets were to be taken once daily throughout the trial. The sitagliptin tablet was to be swallowed whole and not broken or chewed and could be taken with or without food.

    Arm title
    Sitagliptin 100 mg
    Arm description
    Subjects were to take sitagliptin 100 mg tablets once daily from weeks 1 - 78. In addition, subjects were to take semaglutide placebo tablets once daily from weeks 1 - 78.
    Arm type
    Active comparator

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Januvia®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin 100 mg tablets were to be taken once daily throughout the trial without any dose escalation or dose adjustment. The sitagliptin tablet was to be swallowed whole and not broken or chewed and could be taken with or without food.

    Investigational medicinal product name
    Semaglutide placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Semaglutide placebo tablets were to be taken once daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The trial product could be taken with up to half a glass of water (approximately 120 mL/4 fluid oz) and was to be swallowed whole and not broken or chewed. Oral medication other than trial product could only be taken 30 minutes after administration of trial product.

    Number of subjects in period 1
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Started
    466
    465
    465
    467
    Completed
    433
    436
    438
    451
    Not completed
    33
    29
    27
    16
         Adverse event, serious fatal
    5
    4
    1
    3
         Consent withdrawn by subject
    18
    18
    17
    8
         Unclassified
    1
    -
    2
    -
         Lost to follow-up
    9
    7
    7
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oral semaglutide 3 mg
    Reporting group description
    Subjects were to take oral semaglutide 3 mg tablets once daily from weeks 1 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Oral semaglutide 7 mg
    Reporting group description
    Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from weeks 1 - 78: 3 mg from weeks 1 - 4 and 7 mg from weeks 5 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from weeks 1 - 78: 3 mg from weeks 1 - 4, 7 mg from weeks 5 - 8 and 14 mg from weeks 9 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    Subjects were to take sitagliptin 100 mg tablets once daily from weeks 1 - 78. In addition, subjects were to take semaglutide placebo tablets once daily from weeks 1 - 78.

    Reporting group values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg Total
    Number of subjects
    466 465 465 467 1863
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    339 335 342 346 1362
        From 65-84 years
    127 130 123 121 501
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    58 ± 10 58 ± 10 57 ± 10 58 ± 10 -
    Gender Categorical
    Units: Subjects
        Female
    212 220 218 229 879
        Male
    254 245 247 238 984
    Glycosylated haemoglobin (HbA1c)
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    8.3 ± 1.0 8.4 ± 1.0 8.3 ± 0.9 8.3 ± 0.9 -
    Body weight
    Units: Kg
        arithmetic mean (standard deviation)
    91.6 ± 22.0 91.3 ± 20.8 91.2 ± 21.7 90.9 ± 21.0 -

    End points

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    End points reporting groups
    Reporting group title
    Oral semaglutide 3 mg
    Reporting group description
    Subjects were to take oral semaglutide 3 mg tablets once daily from weeks 1 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Oral semaglutide 7 mg
    Reporting group description
    Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from weeks 1 - 78: 3 mg from weeks 1 - 4 and 7 mg from weeks 5 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from weeks 1 - 78: 3 mg from weeks 1 - 4, 7 mg from weeks 5 - 8 and 14 mg from weeks 9 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    Subjects were to take sitagliptin 100 mg tablets once daily from weeks 1 - 78. In addition, subjects were to take semaglutide placebo tablets once daily from weeks 1 - 78.

    Primary: Change in HbA1c (in-trial observation period): Week 26

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    End point title
    Change in HbA1c (in-trial observation period): Week 26
    End point description
    Change from baseline (week 0) in glycosylated haemoglobin (HbA1c) was evaluated at week 26. Results are based on the in-trial observation period, which was the time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. Population analysed: The full analysis set (FAS), which comprised all randomised subjects. Number of subjects analysed = number of subjects with available data.
    End point type
    Primary
    End point timeframe
    From baseline to week 26.
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    435
    438
    436
    446
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -0.6 ± 1.0
    -1.1 ± 1.1
    -1.3 ± 1.0
    -0.8 ± 0.9
    Statistical analysis title
    Oral semaglutide 14 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an analysis of covariance (ANCOVA) model with trial product, region and stratification factor as fixed effects and the baseline HbA1c value as the covariate.
    Comparison groups
    Oral semaglutide 14 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    882
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    < 0.0001 [2]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.4
    Notes
    [1] - This hypothesis was controlled for multiplicity. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). A value of 0.3% (the non-inferiority margin) was added to imputed values at week 26 for the oral semaglutide treatment arm only.
    [2] - Unadjusted two-sided p-value for test of no difference from the non-inferiority margin (non-inferiority).
    Statistical analysis title
    Oral semaglutide 14 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with trial product, region and stratification factor as fixed effects and the baseline HbA1c value as the covariate.
    Comparison groups
    Oral semaglutide 14 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    882
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.0001 [4]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.4
    Notes
    [3] - This hypothesis was controlled for multiplicity. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand).
    [4] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).
    Statistical analysis title
    Oral semaglutide 7 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with trial product, region and stratification factor as fixed effects and the baseline HbA1c value as the covariate.
    Comparison groups
    Oral semaglutide 7 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    884
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    P-value
    < 0.0001 [6]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    -0.1
    Notes
    [5] - This hypothesis was controlled for multiplicity. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). A value of 0.3% (the non-inferiority margin) was added to imputed values at week 26 for the oral semaglutide treatment arm only.
    [6] - Unadjusted two-sided p-value for test of no difference from the non-inferiority margin (non-inferiority).
    Statistical analysis title
    Oral semaglutide 7 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with trial product, region and stratification factor as fixed effects and the baseline HbA1c value as the covariate.
    Comparison groups
    Oral semaglutide 7 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    884
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    < 0.0001 [8]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    -0.1
    Notes
    [7] - This hypothesis was controlled for multiplicity. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand).
    [8] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).
    Statistical analysis title
    Oral semaglutide 3 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with trial product, region and stratification factor as fixed effects and the baseline HbA1c value as the covariate.
    Comparison groups
    Oral semaglutide 3 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    881
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [9]
    P-value
    = 0.0856 [10]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.3
    Notes
    [9] - This hypothesis was controlled for multiplicity, but could not be confirmed. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). A value of 0.3% (the non-inferiority margin) was added to imputed values at week 26 for the oral semaglutide treatment arm only.
    [10] - Unadjusted two-sided p-value for test of no difference from the non-inferiority margin (non-inferiority).
    Statistical analysis title
    Oral semaglutide 3 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with trial product, region and stratification factor as fixed effects and the baseline HbA1c value as the covariate.
    Comparison groups
    Oral semaglutide 3 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    881
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.008 [12]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.3
    Notes
    [11] - This hypothesis was not controlled for multiplicity, since the non-inferiority test of change in HbA1c for oral semaglutide 3 mg versus sitagliptin 100 mg could not be confirmed. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand).
    [12] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).

    Primary: Change in HbA1c (on treatment without rescue medication observation period): Week 26

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    End point title
    Change in HbA1c (on treatment without rescue medication observation period): Week 26
    End point description
    Change from baseline (week 0) in HbA1c was evaluated at week 26. Results are based on the on treatment without rescue medication observation period, which was the time period when a subject was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Primary
    End point timeframe
    From baseline to week 26
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    391
    409
    398
    419
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -0.6 ± 1.0
    -1.2 ± 1.1
    -1.4 ± 1.0
    -0.8 ± 0.9
    Statistical analysis title
    Oral semaglutide 14 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a mixed model for repeated measurements (MMRM) that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 14 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    817
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [13]
    P-value
    = 0.0001 [14]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    -0.5
    Notes
    [13] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand). Non-inferiority margin = 0.3%.
    [14] - Unadjusted two-sided p-value for test of no difference from the non-inferiority margin (non-inferiority).
    Statistical analysis title
    Oral semaglutide 14 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a mixed MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 14 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    817
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.0001 [16]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    -0.5
    Notes
    [15] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand).
    [16] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).
    Statistical analysis title
    Oral semaglutide 7 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a mixed MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 7 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    828
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [17]
    P-value
    < 0.0001 [18]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    -0.2
    Notes
    [17] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand). Non-inferiority margin = 0.3%.
    [18] - Unadjusted two-sided p-value for test of no difference from the non-inferiority margin (non-inferiority).
    Statistical analysis title
    Oral semaglutide 7 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a mixed MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 7 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    828
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    P-value
    < 0.0001 [20]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    -0.2
    Notes
    [19] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand).
    [20] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).
    Statistical analysis title
    Oral semaglutide 3 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a mixed MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 3 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    810
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [21]
    P-value
    = 0.3851 [22]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.4
    Notes
    [21] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand). Non-inferiority margin = 0.3%.
    [22] - Unadjusted two-sided p-value for test of no difference from the non-inferiority margin (non-inferiority).
    Statistical analysis title
    Oral semaglutide 3 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a mixed MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline HbA1c value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 3 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    810
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.0001 [24]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.4
    Notes
    [23] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand).
    [24] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).

    Secondary: Change in body weight (in-trial observation period): Week 26

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    End point title
    Change in body weight (in-trial observation period): Week 26
    End point description
    Change from baseline (week 0) in body weight was evaluated at week 26. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    438
    440
    439
    447
    Units: Kg
        arithmetic mean (standard deviation)
    -1.2 ± 3.2
    -2.2 ± 3.9
    -3.1 ± 3.8
    -0.6 ± 3.2
    Statistical analysis title
    Oral semaglutide 14 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with trial product, region and stratification factor as fixed effects and the baseline body weight value as the covariate.
    Comparison groups
    Oral semaglutide 14 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    < 0.0001 [26]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    -2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3
         upper limit
    -2
    Notes
    [25] - This hypothesis was controlled for multiplicity. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand).
    [26] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).
    Statistical analysis title
    Oral semaglutide 7 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with trial product, region and stratification factor as fixed effects and the baseline body weight value as the covariate.
    Comparison groups
    Oral semaglutide 7 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    887
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    < 0.0001 [28]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    -1.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    -1.1
    Notes
    [27] - This hypothesis was controlled for multiplicity. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand).
    [28] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).
    Statistical analysis title
    Oral semaglutide 3 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a pattern mixture model that used multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with trial product, region and stratification factor as fixed effects and the baseline body weight value as the covariate.
    Comparison groups
    Oral semaglutide 3 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    885
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    = 0.0185 [30]
    Method
    Pattern mixture model
    Parameter type
    Mean treatment difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    -0.1
    Notes
    [29] - This hypothesis was not controlled for multiplicity, since the non-inferiority test of change in HbA1c for oral semaglutide 3 mg versus sitagliptin 100 mg could not be confirmed. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand).
    [30] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).

    Secondary: Change in body weight (on treatment without rescue medication observation period): Week 26

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    End point title
    Change in body weight (on treatment without rescue medication observation period): Week 26
    End point description
    Change from baseline (week 0) in body weight was evaluated at week 26. Results are based on the on treatment without rescue medication observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    394
    411
    401
    420
    Units: Kg
        arithmetic mean (standard deviation)
    -1.2 ± 3.3
    -2.2 ± 4.0
    -3.2 ± 3.8
    -0.6 ± 3.2
    Statistical analysis title
    Oral semaglutide 14 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline body weight value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 14 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    821
    Analysis specification
    Pre-specified
    Analysis type
    superiority [31]
    P-value
    < 0.0001 [32]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    -2.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.1
         upper limit
    -2.1
    Notes
    [31] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand).
    [32] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).
    Statistical analysis title
    Oral semaglutide 7 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline body weight value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 7 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    831
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    < 0.0001 [34]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    -1.1
    Notes
    [33] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand).
    [34] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).
    Statistical analysis title
    Oral semaglutide 3 mg versus sitagliptin 100 mg
    Statistical analysis description
    The analysis was based on a MMRM that assumed data to be missing at random. As dependent variables, the MMRM model included all post-baseline values collected at scheduled visits up to and including week 26. The independent effects were trial product, region and stratification factor as categorical fixed effects and the baseline body weight value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 3 mg v Sitagliptin 100 mg
    Number of subjects included in analysis
    814
    Analysis specification
    Pre-specified
    Analysis type
    superiority [35]
    P-value
    = 0.0257 [36]
    Method
    MMRM
    Parameter type
    Mean treatment difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    -0.1
    Notes
    [35] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand).
    [36] - Unadjusted two-sided p-value for test of no difference from 0 (superiority).

    Secondary: Change in FPG: Week 26

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    End point title
    Change in FPG: Week 26
    End point description
    Change from baseline (week 0) in fasting plasma glucose (FPG) was evaluated at week 26. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed (n) = number of subjects with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    466
    465
    465
    467
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline (n=464, 463, 462, 464)
    9.67 ± 2.80
    9.45 ± 2.38
    9.32 ± 2.50
    9.53 ± 2.33
        Change from baseline (n=433, 436, 433, 443)
    -0.83 ± 2.69
    -1.17 ± 2.54
    -1.67 ± 2.60
    -0.90 ± 2.32
    No statistical analyses for this end point

    Secondary: Subjects who achieve (yes/no) HbA1c <7.0% (53 mmol/mol), ADA target: Week 26

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    End point title
    Subjects who achieve (yes/no) HbA1c <7.0% (53 mmol/mol), ADA target: Week 26
    End point description
    Subjects who achieved (yes/no) HbA1c <7.0% (American Diabetes Association (ADA) target), was evaluated at week 26. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of treatment
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    435
    438
    436
    446
    Units: Subjects
        Yes
    116
    192
    246
    144
        No
    319
    246
    190
    302
    No statistical analyses for this end point

    Secondary: Subjects who achieve (yes/no) HbA1c <7.0% (53 mmol/mol), ADA target: Week 52

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    End point title
    Subjects who achieve (yes/no) HbA1c <7.0% (53 mmol/mol), ADA target: Week 52
    End point description
    Subjects who achieved (yes/no) HbA1c <7.0% ADA target, was evaluated at week 52. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 52 weeks of treatment
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    427
    431
    434
    436
    Units: Subjects
        Yes
    113
    168
    238
    138
        No
    314
    263
    196
    298
    No statistical analyses for this end point

    Secondary: Subjects who achieve (yes/no) HbA1c <7.0% (53 mmol/mol), ADA target: Week 78

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    End point title
    Subjects who achieve (yes/no) HbA1c <7.0% (53 mmol/mol), ADA target: Week 78
    End point description
    Subjects who achieved (yes/no) HbA1c <7.0% ADA target, was evaluated at week 78. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After 78 weeks of treatment
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    421
    424
    425
    439
    Units: Subjects
        Yes
    113
    165
    191
    129
        No
    308
    259
    234
    310
    No statistical analyses for this end point

    Secondary: Change in HbA1c: Week 52

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    End point title
    Change in HbA1c: Week 52
    End point description
    Change from baseline (week 0) in HbA1c was evaluated at week 52. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    427
    431
    434
    436
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -0.6 ± 1.1
    -1.0 ± 1.2
    -1.2 ± 1.1
    -0.7 ± 1.1
    No statistical analyses for this end point

    Secondary: Change in HbA1c: Week 78

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    End point title
    Change in HbA1c: Week 78
    End point description
    Change from baseline (week 0) in HbA1c was evaluated at week 52. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 78
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    421
    424
    425
    439
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -0.6 ± 1.1
    -0.9 ± 1.3
    -1.1 ± 1.1
    -0.7 ± 1.1
    No statistical analyses for this end point

    Secondary: Change in body weight: Week 52

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    End point title
    Change in body weight: Week 52
    End point description
    Change from baseline (week 0) in body weight was evaluated at week 52. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    428
    433
    435
    437
    Units: Kg
        arithmetic mean (standard deviation)
    -1.6 ± 4.1
    -2.5 ± 4.9
    -3.5 ± 4.7
    -0.7 ± 3.7
    No statistical analyses for this end point

    Secondary: Change in body weight: Week 78

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    End point title
    Change in body weight: Week 78
    End point description
    Change from baseline (week 0) in body weight was evaluated at week 78. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 78
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    425
    425
    428
    443
    Units: Kg
        arithmetic mean (standard deviation)
    -1.8 ± 4.9
    -2.8 ± 5.4
    -3.2 ± 4.9
    -1.0 ± 4.1
    No statistical analyses for this end point

    Secondary: Change in FPG: Week 52

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    End point title
    Change in FPG: Week 52
    End point description
    Change from baseline (week 0) in FPG was evaluated at week 52. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    419
    429
    432
    433
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.98 ± 2.78
    -1.28 ± 2.62
    -1.75 ± 2.57
    -1.03 ± 2.60
    No statistical analyses for this end point

    Secondary: Change in FPG: Week 78

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    End point title
    Change in FPG: Week 78
    End point description
    Change from baseline (week 0) in FPG was evaluated at week 78. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 78
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    418
    419
    419
    434
    Units: mmol/L
        arithmetic mean (standard deviation)
    -1.07 ± 3.21
    -1.11 ± 2.92
    -1.65 ± 2.71
    -0.91 ± 2.59
    No statistical analyses for this end point

    Secondary: Number of treatment emergent adverse events (TEAEs) during exposure to trial product

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    End point title
    Number of treatment emergent adverse events (TEAEs) during exposure to trial product
    End point description
    TEAEs were recorded during the exposure to trial products. Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period: Time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Results are based on the safety analysis set, which included all randomised subjects who received at least one dose of trial product.
    End point type
    Secondary
    End point timeframe
    Assessed up to approximately 83 weeks
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    466
    464
    465
    466
    Units: Events
    1774
    1686
    1824
    1852
    No statistical analyses for this end point

    Secondary: Number of treatment emergent severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes during exposure to trial product

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    End point title
    Number of treatment emergent severe or blood glucose (BG) confirmed symptomatic hypoglycaemic episodes during exposure to trial product
    End point description
    Treatment emergent severe or BG confirmed symptomatic hypoglycaemic episodes were recorded during exposure to trial products. Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Results are based on the safety analysis set.
    End point type
    Secondary
    End point timeframe
    Assessed up to approximately 83 weeks
    End point values
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Number of subjects analysed
    466
    464
    465
    466
    Units: Episodes
    56
    42
    60
    76
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Weeks 0 – 83 (78 weeks treatment period + 5 weeks follow-up period). All presented AEs are TEAEs.
    Adverse event reporting additional description
    Results are based on the safety analysis set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Oral semaglutide 3 mg
    Reporting group description
    Subjects were to take oral semaglutide 3 mg tablets once daily from weeks 1 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Oral semaglutide 7 mg
    Reporting group description
    Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from weeks 1 - 78: 3 mg from weeks 1 - 4 and 7 mg from weeks 5 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from weeks 1 - 78: 3 mg from weeks 1 - 4, 7 mg from weeks 5 - 8 and 14 mg from weeks 9 - 78. In addition, subjects were to take sitagliptin placebo tablets once daily from weeks 1 - 78.

    Reporting group title
    Sitagliptin 100 mg
    Reporting group description
    Subjects were to take sitagliptin 100 mg tablets once daily from weeks 1 - 78. In addition, subjects were to take semaglutide placebo tablets once daily from weeks 1 - 78.

    Serious adverse events
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    64 / 466 (13.73%)
    47 / 464 (10.13%)
    44 / 465 (9.46%)
    58 / 466 (12.45%)
         number of deaths (all causes)
    4
    1
    1
    3
         number of deaths resulting from adverse events
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm malignant
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    2 / 466 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal cavity cancer
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pancreatic neuroendocrine tumour
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 466 (0.43%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Essential hypertension
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hospitalisation
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laparoscopic surgery
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia repair
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Complication associated with device
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    1 / 465 (0.22%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyp
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 466 (0.43%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia, obstructive
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 466 (0.00%)
    2 / 464 (0.43%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    3 / 466 (0.64%)
    3 / 464 (0.65%)
    1 / 465 (0.22%)
    2 / 466 (0.43%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 466 (0.64%)
    2 / 464 (0.43%)
    1 / 465 (0.22%)
    4 / 466 (0.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    2 / 466 (0.43%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    2 / 466 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 466 (0.64%)
    1 / 464 (0.22%)
    2 / 465 (0.43%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 466 (0.21%)
    2 / 464 (0.43%)
    1 / 465 (0.22%)
    2 / 466 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial fibrosis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 466 (0.43%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem stroke
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic inflammatory demyelinating polyradiculoneuropathy
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    2 / 466 (0.43%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    3 / 466 (0.64%)
    0 / 464 (0.00%)
    2 / 465 (0.43%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    2 / 465 (0.43%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exostosis of external ear canal
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract diabetic
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Conjunctival irritation
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic retinopathy
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinopathy proliferative
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    2 / 465 (0.43%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Barrett's oesophagus
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    3 / 465 (0.65%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    3 / 466 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    2 / 465 (0.43%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    2 / 466 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic hepatic failure
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cirrhosis alcoholic
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-alcoholic steatohepatitis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    3 / 465 (0.65%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Haematuria
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypopituitarism
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    1 / 465 (0.22%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic amyotrophy
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 466 (0.43%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 466 (0.64%)
    2 / 464 (0.43%)
    3 / 465 (0.65%)
    2 / 466 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 466 (0.64%)
    0 / 464 (0.00%)
    2 / 465 (0.43%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurosyphilis
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    2 / 466 (0.43%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 466 (0.64%)
    1 / 464 (0.22%)
    2 / 465 (0.43%)
    4 / 466 (0.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 466 (0.00%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    2 / 466 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic phlebitis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 466 (0.00%)
    2 / 464 (0.43%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Testicular abscess
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 466 (0.21%)
    1 / 464 (0.22%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 466 (0.21%)
    0 / 464 (0.00%)
    1 / 465 (0.22%)
    0 / 466 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 466 (0.00%)
    0 / 464 (0.00%)
    0 / 465 (0.00%)
    1 / 466 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Sitagliptin 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    222 / 466 (47.64%)
    234 / 464 (50.43%)
    232 / 465 (49.89%)
    239 / 466 (51.29%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    29 / 466 (6.22%)
    24 / 464 (5.17%)
    26 / 465 (5.59%)
    29 / 466 (6.22%)
         occurrences all number
    32
    27
    26
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 466 (6.22%)
    30 / 464 (6.47%)
    36 / 465 (7.74%)
    36 / 466 (7.73%)
         occurrences all number
    37
    40
    50
    57
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    27 / 466 (5.79%)
    24 / 464 (5.17%)
    16 / 465 (3.44%)
    26 / 466 (5.58%)
         occurrences all number
    27
    25
    16
    27
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    44 / 466 (9.44%)
    53 / 464 (11.42%)
    56 / 465 (12.04%)
    37 / 466 (7.94%)
         occurrences all number
    62
    81
    74
    44
    Nausea
         subjects affected / exposed
    34 / 466 (7.30%)
    62 / 464 (13.36%)
    70 / 465 (15.05%)
    31 / 466 (6.65%)
         occurrences all number
    42
    74
    88
    39
    Vomiting
         subjects affected / exposed
    13 / 466 (2.79%)
    27 / 464 (5.82%)
    42 / 465 (9.03%)
    19 / 466 (4.08%)
         occurrences all number
    15
    41
    82
    26
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 466 (4.51%)
    13 / 464 (2.80%)
    20 / 465 (4.30%)
    29 / 466 (6.22%)
         occurrences all number
    29
    17
    25
    32
    Back pain
         subjects affected / exposed
    24 / 466 (5.15%)
    25 / 464 (5.39%)
    24 / 465 (5.16%)
    29 / 466 (6.22%)
         occurrences all number
    35
    31
    25
    35
    Infections and infestations
    Influenza
         subjects affected / exposed
    29 / 466 (6.22%)
    24 / 464 (5.17%)
    18 / 465 (3.87%)
    30 / 466 (6.44%)
         occurrences all number
    35
    28
    21
    35
    Nasopharyngitis
         subjects affected / exposed
    53 / 466 (11.37%)
    49 / 464 (10.56%)
    47 / 465 (10.11%)
    47 / 466 (10.09%)
         occurrences all number
    74
    65
    57
    69
    Upper respiratory tract infection
         subjects affected / exposed
    36 / 466 (7.73%)
    35 / 464 (7.54%)
    26 / 465 (5.59%)
    32 / 466 (6.87%)
         occurrences all number
    53
    50
    34
    49
    Urinary tract infection
         subjects affected / exposed
    29 / 466 (6.22%)
    21 / 464 (4.53%)
    23 / 465 (4.95%)
    26 / 466 (5.58%)
         occurrences all number
    32
    26
    30
    32
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 466 (1.72%)
    14 / 464 (3.02%)
    32 / 465 (6.88%)
    14 / 466 (3.00%)
         occurrences all number
    8
    15
    32
    15

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2015
    The cut off level for repeat testing of increased levels of aminotransferases was updated from alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >10x upper limit of normal (ULN) to >5x ULN. The rationale was to prompt follow-up of potential clinically significant aminotransferase levels. In addition several sections were updated to add clarity, i.e. stratification, drug accountability, electrocardiogram (ECG) reporting, antibodies and safety reporting.
    23 Dec 2016
    Eye examinations and additional data collection for diabetic retinopathy were introduced along with additional minor clarifications.

    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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