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    Clinical Trial Results:
    Efficacy and Safety of Oral Semaglutide versus Empagliflozin in Subjects with Type 2 Diabetes Mellitus. A 52-week Randomised, Open-label, Active-controlled Trial

    Summary
    EudraCT number
    		 2015-005209-36
    Trial protocol
    		 HU   GR   PL   ES   HR   IT  
    Global end of trial date
    08 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Mar 2019
    First version publication date
    24 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9924-4223
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02863328
    WHO universal trial number (UTN)
    		 U1111-1176-6006
    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
    03 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    08 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 14 mg oral semaglutide versus 25 mg empagliflozin, both in combination with metformin, on glycaemic control in subjects with type 2 diabetes mellitus.
    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 continued on a stable daily dose of anti-diabetic background metformin (≥1500 mg or maximum tolerated dose as documented in the subject medical record) throughout the trial.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    10 Aug 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: 52
    Country: Number of subjects enrolled
    Brazil: 61
    Country: Number of subjects enrolled
    Spain: 70
    Country: Number of subjects enrolled
    Greece: 51
    Country: Number of subjects enrolled
    Croatia: 36
    Country: Number of subjects enrolled
    Hungary: 46
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Poland: 65
    Country: Number of subjects enrolled
    Russian Federation: 60
    Country: Number of subjects enrolled
    Serbia: 51
    Country: Number of subjects enrolled
    Thailand: 41
    Country: Number of subjects enrolled
    United States: 242
    Worldwide total number of subjects
    821
    EEA total number of subjects
    314
    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)
    606
    From 65 to 84 years
    215
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 108 sites in 12 countries as follows: Argentina (4), Brazil (3), Croatia (4), Greece (7), Hungary (7), Italy (5), Poland (6), Russian Federation (6), Serbia (5), Spain (8), Thailand (3), United States (46). 1 site each in Croatia and Italy, and 2 sites in the United States screened, but didn't randomise any subjects.

    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
    		 Not blinded
    Blinding implementation details
    The trial was an open label study. Only the clinical study group remained blinded throughout the conduct of the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oral semaglutide 14 mg
    Arm description
    		 Subjects received once-daily oral semaglutide tablets for 52 weeks. Subjects started oral semaglutide at 3 mg and were dose escalated in 4-week increments until the final maintenance dose of 14 mg once-daily was reached (i.e. 3 mg from week 0 to week 4, 7 mg from week 4 to week 8, 14 mg from week 8 to week 52).
    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
    Oral semaglutide 3 mg was administered from week 0 to week 4, as part of dose escalation regimen. The tablet was taken once-daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The tablet was taken with up to a half a glass of water (approximately 120 mL/4 fluid oz) and was swallowed whole and not broken or chewed. Oral medication other than trial product could be taken 30 minutes after administration of trial product.

    Investigational medicinal product name
    Semglutide 7 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral semaglutide 7 mg was administered from week 4 to week 8, as part of dose escalation regimen. The tablet was taken once-daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The tablet was taken with up to a half a glass of water (approximately 120 mL/4 fluid oz) and was swallowed whole and not broken or chewed. Oral medication other than trial product could be taken 30 minutes after administration of trial product.

    Investigational medicinal product name
    Semglutide 14 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral semaglutide 14 mg was administered from week 8 to week 52, once-daily in the morning. The tablet was taken in a fasting state and at least 30 minutes before the first meal of the day. The tablet was taken with up to a half a glass of water (approximately 120 mL/4 fluid oz) and was swallowed whole and not broken or chewed. Oral medication other than trial product could be taken 30 minutes after administration of trial product.

    Arm title
    		 Empagliflozin 25 mg
    Arm description
    		 Subjects received once-daily empagliflozin tablets for 52 weeks. Subjects started empagliflozin at 10 mg for 8 weeks. The subjects were treated with empagliflozin 25 mg from week 8 until week 52.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Jardiance 10 mg
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin 10 mg tablet was to be taken once-daily in the morning from week 0 to week 8, as part of dose escalation regimen. The tablet was to be swallowed whole with water and it could be taken with or without food.

    Investigational medicinal product name
    Empagliflozin
    Investigational medicinal product code
    Other name
    Jardiance 25 mg
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Empagliflozin 25 mg tablet was to be taken once-daily in the morning from week 8 to week 52. The tablet was to be swallowed whole with water and it could be taken with or without food.

    Number of subjects in period 1
    		Oral semaglutide 14 mg Empagliflozin 25 mg
    Started
    411
    410
    Completed
    400
    387
    Not completed
    11
    23
         Consent withdrawn by subject
    7
    12
         Lost to follow-up
    4
    10
         Died
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 Subjects received once-daily oral semaglutide tablets for 52 weeks. Subjects started oral semaglutide at 3 mg and were dose escalated in 4-week increments until the final maintenance dose of 14 mg once-daily was reached (i.e. 3 mg from week 0 to week 4, 7 mg from week 4 to week 8, 14 mg from week 8 to week 52).

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Subjects received once-daily empagliflozin tablets for 52 weeks. Subjects started empagliflozin at 10 mg for 8 weeks. The subjects were treated with empagliflozin 25 mg from week 8 until week 52.

    Reporting group values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg Total
    Number of subjects
    		 411 410 821
    Age Categorical
    Units: Subjects
        Adults (18-65 years)
    		 306 300 606
        From 65-75 years
    		 92 98 190
        From 75-85 years
    		 13 12 25
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57 ( 10 ) 58 ( 10 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 205 201 406
        Male
    		 206 209 415
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 8.1 ( 0.9 ) 8.1 ( 0.9 ) -
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 91.9 ( 20.5 ) 91.3 ( 20.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 Subjects received once-daily oral semaglutide tablets for 52 weeks. Subjects started oral semaglutide at 3 mg and were dose escalated in 4-week increments until the final maintenance dose of 14 mg once-daily was reached (i.e. 3 mg from week 0 to week 4, 7 mg from week 4 to week 8, 14 mg from week 8 to week 52).

    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 Subjects received once-daily empagliflozin tablets for 52 weeks. Subjects started empagliflozin at 10 mg for 8 weeks. The subjects were treated with empagliflozin 25 mg from week 8 until week 52.

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

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    End point title
    		 Change in HbA1c (in-trial observation period)
    End point description
    Observed mean change from baseline (week 0) to week 26 in glycosylated haemoglobin (HbA1c). The endpoint was evaluated based on data from the in-trial observation period. In trial observation period: the time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication or premature discontinuation of trial product. Results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data at week 26.
    End point type
    Primary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    392
    395
    Units: %-point
        arithmetic mean (standard deviation)
    -1.3 ( 1.1 )
    -0.9 ( 0.9 )
    Statistical analysis title
    		 Oral semaglutide 14 mg vs. Empagliflozin
    Statistical analysis description
    Analysed using an ANCOVA model with treatment and region as categorical fixed effects and baseline value as covariate for each of the 1000 imputed complete datasets, and pooled by Rubin's rule to draw inference. Hypothesis: H0: μ ≥0.4%-points against Ha: μ <0.4%-points. (μ denotes mean treatment difference). HbA1c non-inferiority, using a non-inferiority margin of 0.4%-points. A value of 0.4% was added to imputed values at week 26 for the oral semaglutide treatment arms only.
    Comparison groups
    Oral semaglutide 14 mg v Empagliflozin 25 mg
    Number of subjects included in analysis
    787
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.3
    Notes
    [1] - The analysis was for the treatment policy estimand based on data from in-trial observation period. "Subjects in this analysis"=number of subjects with available data at week 26; all subjects in the FAS (N=821) contributed to the analysis.
    [2] - Unadjusted two-sided p-value for test of no difference from the non-inferiority margin.
    Statistical analysis title
    		 Oral semaglutide 14 mg vs. empagliflozin 25 mg
    Statistical analysis description
    Change from baseline was analysed using an ANCOVA model with treatment and region as categorical fixed effects and baseline value as covariate for each of the 1000 imputed complete datasets, and pooled by Rubin's rule to draw inference. Hypothesis: H0: μ ≥0.0%-points against Ha: μ <0.0%-points (μ denotes mean treatment difference).
    Comparison groups
    Oral semaglutide 14 mg v Empagliflozin 25 mg
    Number of subjects included in analysis
    787
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.3
    Notes
    [3] - The analysis was for the treatment policy estimand based on data from in-trial observation period. "Subjects in this analysis"=number of subjects with available data at week 26; all subjects in the FAS (N=821) contributed to the analysis.
    [4] - Unadjusted two-sided p-value for test of no difference from 0.

    Primary: Change in HbA1c (on-treatment observation period)

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    End point title
    		 Change in HbA1c (on-treatment observation period)
    End point description
    Observed mean change from baseline (week 0) to week 26 in HbA1c. The endpoint was analysed based on data from the on-treatment without rescue medication observation period. On-treatment without rescue medication observation period: the time period when a subject was on treatment with trial product, excluding any period after initiation of rescue medication. The results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data.
    End point type
    Primary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    347
    378
    Units: %-points
        arithmetic mean (standard deviation)
    -1.5 ( 1.1 )
    -0.9 ( 0.9 )
    Statistical analysis title
    		 Oral semaglutide 14 mg vs. epagliflozin 25 mg
    Statistical analysis description
    Changes from baseline were analysed using a mixed model for repeated measurements model with treatment and region as categorical fixed effects and baseline value as covariate, all nested within visit, and an unstructured residual covariance matrix. Hypothesis: H0: μ ≥0.4%-points against Ha: μ <0.4%-points. (μ denotes mean treatment difference). HbA1c non-inferiority, using a non-inferiority margin of 0.4%-points.
    Comparison groups
    Oral semaglutide 14 mg v Empagliflozin 25 mg
    Number of subjects included in analysis
    725
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    P-value
    		 < 0.0001 [6]
    Method
    		 Mixed model for repeated measurements
    Parameter type
    		 Treatment difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.4
    Notes
    [5] - The analysis was for the hypothetical estimand based on data from on-treatment observation period. "Subjects in this analysis"=number of subjects with available data at week 26; all subjects in the FAS (N=821) contributed to the analysis.
    [6] - Unadjusted two-sided p-value for test of no difference from the non-inferiority margin.
    Statistical analysis title
    		 Oral semaglutide 14 mg vs. empagliflozin 25 mg
    Statistical analysis description
    Changes from baseline were analysed using a mixed model for repeated measurements model with treatment and region as categorical fixed effects and baseline value as covariate, all nested within visit, and an unstructured residual covariance matrix. The null hypothesis (H0) and the alternate hypothesis (HA) were: H0: μ ≥0.0%-points against HA: μ <0.0%. (μ denotes mean treatment difference).
    Comparison groups
    Oral semaglutide 14 mg v Empagliflozin 25 mg
    Number of subjects included in analysis
    725
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Treatment difference
    Parameter type
    		 Treatment difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.4
    Notes
    [7] - The analysis was for the hypothetical estimand based on data from on-treatment observation period. "Subjects in this analysis"=number of subjects with available data; all subjects in the FAS (N=821) contributed to the analysis.
    [8] - Unadjusted two-sided p-value for test of no difference from 0.

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

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    End point title
    		 Change in body weight (in-trial observation period)
    End point description
    Observed mean change from baseline (week 0) to week 26 in body weight. The endpoint was evaluated based on data from the in-trial observation period. Results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    393
    396
    Units: kg
        arithmetic mean (standard deviation)
    -3.9 ( 4.4 )
    -3.8 ( 3.8 )
    Statistical analysis title
    		 Oral semaglutide 14 mg vs. empagliflozin 25 mg
    Statistical analysis description
    Change from baseline was analysed using an ANCOVA model with treatment and region as categorical fixed effects and baseline value as covariate for each of the 1000 imputed complete datasets, and pooled by Rubin's rule to draw inference. Hypothesis tested: H0: μ ≥0.0 kg against Ha: μ <0.0 kg (μ denotes mean treatment difference).
    Comparison groups
    Oral semaglutide 14 mg v Empagliflozin 25 mg
    Number of subjects included in analysis
    789
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.7593 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.5
    Notes
    [9] - Analysis was for the treatment policy estimand based on data from in-trial observation period. "Subjects in this analysis"=number of subjects with available data at week 26; all subjects in the FAS (N=821) contributed to the analysis.
    [10] - Unadjusted two-sided p-value for test of no difference from 0.

    Secondary: Change in body weight (on-treatment observation period)

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    End point title
    		 Change in body weight (on-treatment observation period)
    End point description
    Observed mean change from baseline (week 0) to week 26 in body weight. The endpoint was analysed based on data from the on-treatment without rescue medication observation period. Full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    348
    378
    Units: kg
        arithmetic mean (standard deviation)
    -4.3 ( 4.4 )
    -3.9 ( 3.8 )
    Statistical analysis title
    		 Oral semagltide 14 mg vs. empagliflozin
    Statistical analysis description
    Changes from baseline were analysed using a mixed model for repeated measurements model with treatment and region as categorical fixed effects and baseline value as covariate, all nested within visit, and an unstructured residual covariance matrix.
    Comparison groups
    Oral semaglutide 14 mg v Empagliflozin 25 mg
    Number of subjects included in analysis
    726
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.1358 [12]
    Method
    		 Mixed model for repeated measurements
    Parameter type
    		 Treatment difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 0.1
    Notes
    [11] - Analysis was for the treatment policy estimand based on data from on-treatment observation period. "Subjects in this analysis"=number of subjects with available data at week 26; all subjects in the FAS (N=821) contributed to the analysis.
    [12] - Unadjusted two-sided p-value for test of no difference from 0.

    Secondary: Change in HbA1c (52 weeks)

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    End point title
    		 Change in HbA1c (52 weeks)
    End point description
    Observed mean change from baseline (week 0) to week 52 in HbA1c. The endpoint was evaluated for the treatment policy estimand based on data from the in-trial observation period. Results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data. The endpoint was evaluated for the treatment policy estimand based on data from the in-trial observation period.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    384
    382
    Units: percentage
        arithmetic mean (standard deviation)
    -1.3 ( 1.2 )
    -0.9 ( 1.0 )
    No statistical analyses for this end point

    Secondary: Change in body weight (52 weeks)

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    End point title
    		 Change in body weight (52 weeks)
    End point description
    Observed mean change from baseline (week 0) to week 52 in body weight. The endpoint was evaluated for the treatment policy estimand based on data from the in-trial observation period. Results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    386
    383
    Units: kg
        arithmetic mean (standard deviation)
    -4.0 ( 5.5 )
    -3.7 ( 4.3 )
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose (week 26)

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    End point title
    		 Change in fasting plasma glucose (week 26)
    End point description
    Observed mean change from baseline (week 0) to week 26 in fasting plasma glucose. The endpoint was evaluated for the treatment policy estimand based on data from the in-trial observation period. Results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    388
    391
    Units: mmol/L
        arithmetic mean (standard deviation)
    -2.01 ( 2.56 )
    -2.08 ( 2.17 )
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose (week 52)

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    End point title
    		 Change in fasting plasma glucose (week 52)
    End point description
    Observed mean change from baseline (week 0) to week 52 in fasting plasma glucose. The endpoint was evaluated for the treatment policy estimand based on data from the in-trial observation period. Results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    380
    378
    Units: mmol/L
        arithmetic mean (standard deviation)
    -2.04 ( 2.50 )
    -2.14 ( 2.36 )
    No statistical analyses for this end point

    Secondary: Achieved HbA1c <7.0 % (53 mmol/mol) American Diabetes Association (ADA) target (yes/no) (week 26)

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    End point title
    		 Achieved HbA1c <7.0 % (53 mmol/mol) American Diabetes Association (ADA) target (yes/no) (week 26)
    End point description
    Percentage of subjects achieving HbA1c less than 7.0% (53 mmol/mol) American Diabetes Association (ADA) target at week 26. The endpoint was evaluated for the treatment policy estimand based on data from the in-trial observation period. Results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    After week 26
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    392
    395
    Units: Percentage of subjects
    number (not applicable)
        Yes
    66.8
    40.0
        No
    33.2
    60.0
    No statistical analyses for this end point

    Secondary: Achieved HbA1c < 7.0 % (53 mmol/mol) American Diabetes Association target (yes/no) (week 52)

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    End point title
    		 Achieved HbA1c < 7.0 % (53 mmol/mol) American Diabetes Association target (yes/no) (week 52)
    End point description
    Percentage of subjects achieving HbA1c less than 7.0% (53 mmol/mol) American Diabetes Association (ADA) target at week 52. The endpoint was evaluated for the treatment policy estimand based on data from the in-trial observation period. Results are based on full analysis set comprised of all randomised subjects. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    After week 52
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    384
    382
    Units: percentage of subjects
    number (not applicable)
        Yes
    66.1
    43.2
        No
    33.9
    56.8
    No statistical analyses for this end point

    Secondary: Number of treatment-emergent adverse events (TEAE)

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    End point title
    		 Number of treatment-emergent adverse events (TEAE)
    End point description
    A treatment-emergent adverse event (TEAE) is defined as an adverse event with onset in the on-treatment observation period (the time period where subjects are considered treated with trial product). The safety analysis set (SAS) included all randomised subjects who received at least one dose of trial product. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    Weeks 0-57
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    410
    409
    Units: Event
        number (not applicable)
    1022
    948
    No statistical analyses for this end point

    Secondary: Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes during exposure to trial product, assessed up to approximately 57 weeks

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    End point title
    		 Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes during exposure to trial product, assessed up to approximately 57 weeks
    End point description
    Hypoglycaemic episodes defined as treatment-emergent if the onset of the episode occurs within the on-treatment observation period. Severe or BG-confirmed symptomatic hypoglycaemia is an episode that is severe according to the American Diabetes Association classification or blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56mg/dL) with symptoms consistent with hypoglycaemia. The safety analysis set (SAS) included all randomised subjects who received at least one dose of trial product. "Number of subjects analysed"=subjects with available data.
    End point type
    Secondary
    End point timeframe
    Weeks 0-57
    End point values
    		 Oral semaglutide 14 mg Empagliflozin 25 mg
    Number of subjects analysed
    410
    409
    Units: Episode
        number (not applicable)
    10
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first trial-related activity after the subject had signed the informed consent until the end of the post-treatment follow-up period (week 52+ 5 weeks of follow-up; until week 57), or until the end of trial for discontinued subjects.
    Adverse event reporting additional description
    A treatment-emergent adverse event (TEAE) is defined as an adverse event with onset in the on-treatment observation period (the time period where subjects are considered treated with trial product). The results are based on the safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Empagliflozin 25 mg
    Reporting group description
    		 N/A

    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 N/A

    Serious adverse events
    		 Empagliflozin 25 mg Oral semaglutide 14 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 409 (9.05%)
    27 / 410 (6.59%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 409 (0.49%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary arterial stent insertion
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Arteriogram coronary
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Back injury
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis postoperative
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 409 (0.24%)
    2 / 410 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 409 (0.73%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 409 (0.24%)
    2 / 410 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CANVAS syndrome
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 410 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypocoagulable state
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Ear haemorrhage
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 410 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head deformity
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perichondritis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 409 (0.24%)
    2 / 410 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Empagliflozin 25 mg Oral semaglutide 14 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 409 (10.76%)
    128 / 410 (31.22%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 409 (3.18%)
    38 / 410 (9.27%)
         occurrences all number
    17
    48
    Nausea
         subjects affected / exposed
    10 / 409 (2.44%)
    81 / 410 (19.76%)
         occurrences all number
    12
    106
    Vomiting
         subjects affected / exposed
    7 / 409 (1.71%)
    30 / 410 (7.32%)
         occurrences all number
    7
    40
    Infections and infestations
    Influenza
         subjects affected / exposed
    21 / 409 (5.13%)
    8 / 410 (1.95%)
         occurrences all number
    23
    8
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 409 (0.49%)
    21 / 410 (5.12%)
         occurrences all number
    2
    21

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2016
    1. Introduction of additional eye examinations and additional data collection on diabetic retinopathy. 2. Added text to highlight the investigator’s responsibility in ensuring evaluation and management of certain risk factors and complications. 3. Clarification of the criteria for completion, withdrawal and lost to follow-up. 4. Other minor corrections and 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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