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    Clinical Trial Results:
    Efficacy and safety of semaglutide once-weekly versus sitagliptin once daily as add-on to metformin and/or thiazolidinedione (TZD) in subjects with type 2 diabetes

    Summary
    EudraCT number
    		 2012-004827-19
    Trial protocol
    		 SE   BG   PT   ES   HU   CZ   NO  
    Global end of trial date
    12 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Nov 2016
    First version publication date
    05 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9535-3626
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01930188
    WHO universal trial number (UTN)
    		 U1111-1135-8730
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Vandtaarnsvej 114, VTB, Soeborg, Denmark, DK2860
    Public contact
    Global Clinical Registry (GCR,1452, Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of once-weekly dosing of two dose levels of semaglutide versus sitagliptin 100 mg once-daily on glycaemic control after 56 weeks of treatment.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, ICH Good Clinical Practice and FDA 21 CFR 312.50 and 56.
    Background therapy
    		 The following compounds were considered as background medication: • Metformin • Thiazolidinedione (TZD) (pioglitazone and rosiglitazone) Subjects were on stable treatment for at least 90 days prior to screening with either metformin ≥ 1500 mg (or maximum tolerated dose), pioglitazone ≥ 30 mg (or maximum tolerated dose), rosiglitazone ≥ 4 mg (or maximum tolerated dose) or a combination of either metformin/pioglitazone or metformin/rosiglitazone (doses as for individual therapies). Subjects upon inclusion continued pre-trial background medication throughout the entire trial. The background medication were maintained at the stable, pre-trial dose and frequency during the whole treatment period unless rescue medication was needed.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    02 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 65
    Country: Number of subjects enrolled
    Bulgaria: 99
    Country: Number of subjects enrolled
    Czech Republic: 49
    Country: Number of subjects enrolled
    Spain: 69
    Country: Number of subjects enrolled
    Hong Kong: 18
    Country: Number of subjects enrolled
    Hungary: 46
    Country: Number of subjects enrolled
    India: 93
    Country: Number of subjects enrolled
    Japan: 140
    Country: Number of subjects enrolled
    Mexico: 63
    Country: Number of subjects enrolled
    Norway: 32
    Country: Number of subjects enrolled
    Portugal: 15
    Country: Number of subjects enrolled
    Romania: 60
    Country: Number of subjects enrolled
    Russian Federation: 133
    Country: Number of subjects enrolled
    Sweden: 58
    Country: Number of subjects enrolled
    Thailand: 39
    Country: Number of subjects enrolled
    Turkey: 87
    Country: Number of subjects enrolled
    Ukraine: 81
    Country: Number of subjects enrolled
    South Africa: 78
    Worldwide total number of subjects
    1225
    EEA total number of subjects
    428
    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)
    993
    From 65 to 84 years
    232
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 124 sites in 18 countries: Argentina: 4; Bulgaria: 10; Czech Republic: 5; Hong Kong: 1; Hungary: 4; India: 11; Japan: 14; Mexico: 5 Norway: 5; Portugal: 6; Romania: 5; Russian Federation: 17; South Africa: 7; Spain: 7: Sweden: 4; Thailand: 4; Turkey: 9; and Ukraine: 6 sites.

    Pre-assignment
    Screening details
    		 Not applicable

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Semaglutide and semaglutide placebo were supplied in similar 1.5 mL pre-filled PDS290 pen-injectors which were visually identical, and were packaged and labelled to fulfil the requirements for double-blind procedures. Equal volumes of semaglutide and semaglutide placebo were administered during treatment, further ensuring blinding during the trial. Sitagliptin and sitagliptin placebo were identical in appearance and were packaged and labelled as per requirements for double-blind procedures.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Semaglutide 0.5 mg + Sitagliptin placebo
    Arm description
    		 Semaglutide 0.5 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide B 1.34 mg/ml PDS290
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Semaglutide (0.5 mg) was administered in the thigh, abdomen, or upper arm, at any time of the day irrespective of meals. The maintenance dose of 0.5 mg was reached after four doses (4 weeks) of 0.25 mg. The maintenance dose of 1.0 mg was reached after four doses (4 weeks) of 0.25 mg, followed by four doses (4 weeks) of 0.5 mg. After the maintenance dose was reached, the dose was not to be changed during the remainder of the trial.

    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 was provided as 100 mg tablets and administered orally once daily at any time of the day irrespective of meals.

    Arm title
    		 Semaglutide 1.0 mg + Sitagliptin placebo
    Arm description
    		 Semaglutide 1.0 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily.
    Arm type
    		 Experimental

    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 was provided as tablets and administered orally once daily at any time of the day

    Investigational medicinal product name
    Semaglutide B 1.34 mg/ml PDS290
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Semaglutide 1.0 mg was administered in the thigh, abdomen, or upper arm, at any time of the day irrespective of meals. The maintenance dose of 1.0 mg was reached after four doses (4 weeks) of 0.25 mg, followed by four doses (4 weeks) of 0.5 mg. After the maintenance dose was reached, the dose was not to be changed during the remainder of the trial.

    Arm title
    		 Sitagliptin + Semaglutide placebo
    Arm description
    		 Subjects were randomised to 2 different sitagliptin arms (sitagliptin + semaglutide placebo 0.5 mg and sitagliptin + semaglutide placebo 1.0 mg). Both arms were pooled together for data analysis. Semaglutide placebo administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin (100 mg) administered orally once daily.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Semaglutide placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Semaglutide placebo was administered in the thigh, abdomen, or upper arm, at any time of the day

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Januvia
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin was provided as 100 mg tablets and administered orally once daily at any time of the day irrespective of meals.

    Number of subjects in period 1
    		Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Started
    409
    409
    407
    Premature discontinuation of treatment
    53 [1]
    61 [2]
    32 [3]
    Completed
    387
    388
    388
    Not completed
    22
    21
    19
         Not completed
    22
    21
    19
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This number represents only those participants who prematurely discontinued the treatment. However, subjects who prematurely discontinued treatment were allowed to continue participation in the trial.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This number represents only those participants who prematurely discontinued the treatment. However, subjects who prematurely discontinued treatment were allowed to continue participation in the trial.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This number represents only those participants who prematurely discontinued the treatment. However, subjects who prematurely discontinued treatment were allowed to continue participation in the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 0.5 mg + Sitagliptin placebo
    Reporting group description
    		 Semaglutide 0.5 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily.

    Reporting group title
    Semaglutide 1.0 mg + Sitagliptin placebo
    Reporting group description
    		 Semaglutide 1.0 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily.

    Reporting group title
    Sitagliptin + Semaglutide placebo
    Reporting group description
    		 Subjects were randomised to 2 different sitagliptin arms (sitagliptin + semaglutide placebo 0.5 mg and sitagliptin + semaglutide placebo 1.0 mg). Both arms were pooled together for data analysis. Semaglutide placebo administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin (100 mg) administered orally once daily.

    Reporting group values
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo Total
    Number of subjects
    		 409 409 407 1225
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 333 332 328 993
        Elderly (From 65-84 years)
    		 76 77 79 232
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.8 ± 10.2 56 ± 9.4 54.6 ± 10.4 -
    Gender Categorical
    Units: Subjects
        Female
    		 202 204 199 605
        Male
    		 207 205 208 620
    HbA1c
    Units: percentage
        arithmetic mean (standard deviation)
    		 8.01 ± 0.92 8.04 ± 0.93 8.17 ± 0.92 -
    Body Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 89.93 ± 20.39 89.21 ± 20.74 89.29 ± 19.67 -
    Fasting Plasma Glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.33 ± 2.38 9.29 ± 2.22 9.6 ± 2.16 -
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 80.63 ± 9.76 80.87 ± 9.08 80.48 ± 8.7 -
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 132.73 ± 16.09 132.56 ± 13.93 132.66 ± 14.58 -

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 0.5 mg + Sitagliptin placebo
    Reporting group description
    		 Semaglutide 0.5 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily.

    Reporting group title
    Semaglutide 1.0 mg + Sitagliptin placebo
    Reporting group description
    		 Semaglutide 1.0 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily.

    Reporting group title
    Sitagliptin + Semaglutide placebo
    Reporting group description
    		 Subjects were randomised to 2 different sitagliptin arms (sitagliptin + semaglutide placebo 0.5 mg and sitagliptin + semaglutide placebo 1.0 mg). Both arms were pooled together for data analysis. Semaglutide placebo administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin (100 mg) administered orally once daily.

    Primary: Change in HbA1c

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    End point title
    		 Change in HbA1c
    End point description
    Change in glycosylated haemoglobin (HbA1c) from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit.
    End point type
    Primary
    End point timeframe
    From Baseline to week 56
    End point values
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Number of subjects analysed
    409
    409
    407
    Units: Percentage
        least squares mean (standard error)
    -1.32 ± 0.05
    -1.61 ± 0.05
    -0.55 ± 0.05
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The post-baseline responses are analysed using a mixed model for repeated measurements with treatment and country as fixed factors and baseline value as covariate, all nested within visit
    Comparison groups
    Semaglutide 1.0 mg + Sitagliptin placebo v Sitagliptin + Semaglutide placebo
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 -0.91
    Notes
    [1] - Non-inferiority was concluded if the upper limit of the two-sided 95% confidence interval for the estimated treatment difference between semaglutide 1.0 mg and sitagliptin was below the pre-specified non-inferiority margin (0.3 %)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The post-baseline responses are analysed using a mixed model for repeated measurements with treatment and country as fixed factors and baseline value as covariate, all nested within visit
    Comparison groups
    Semaglutide 0.5 mg + Sitagliptin placebo v Sitagliptin + Semaglutide placebo
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.92
         upper limit
    		 -0.62
    Notes
    [2] - Non-inferiority was concluded if the upper limit of the two-sided 95% confidence interval for the estimated treatment difference between semaglutide 0.5 mg and sitagliptin was below the pre-specified non-inferiority margin (0.3 %)

    Secondary: Change in Body Weight

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    End point title
    		 Change in Body Weight
    End point description
    Change in body weight from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Number of subjects analysed
    409
    409
    407
    Units: kilogram(s)
        least squares mean (standard error)
    -4.28 ± 0.25
    -6.13 ± 0.25
    -1.93 ± 0.26
    No statistical analyses for this end point

    Secondary: Change in Fasting Plasma Glucose

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    End point title
    		 Change in Fasting Plasma Glucose
    End point description
    Change in fasting plasma glucose from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Number of subjects analysed
    409
    409
    407
    Units: mg/dL
        least squares mean (standard error)
    -37.38 ± 1.79
    -46.72 ± 1.78
    -19.85 ± 1.88
    No statistical analyses for this end point

    Secondary: Change in Systolic and Diastolic Blood Pressure

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    End point title
    		 Change in Systolic and Diastolic Blood Pressure
    End point description
    Change in diastolic and systolic blood pressure from baseline to week 56. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Number of subjects analysed
    409
    409
    407
    Units: mmHg
    least squares mean (standard error)
        Systolic blood presuure
    -5.07 ± 0.64
    -5.61 ± 0.63
    -2.29 ± 0.67
        Diastolic blood pressure
    -2.01 ± 0.42
    -1.91 ± 0.42
    -1.11 ± 0.44
    No statistical analyses for this end point

    Secondary: Change in Patient Reported Outcome (PRO) questionnaire Diabetes Treatment Satisfaction Questionnaire status (DTSQs)

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    End point title
    		 Change in Patient Reported Outcome (PRO) questionnaire Diabetes Treatment Satisfaction Questionnaire status (DTSQs)
    End point description
    Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. Of the 1225 subjects in FAS, 76 in semaglutide 0.5 mg arm, 76 in semaglutide 1.0 mg arm, and 113 in placebo arm had missing data for the endpoint. Missing data imputed from a mixed model for repeated measurements for treatment and country as fixed factors and baseline value as covariate, all nested within visit. The DTSQs questionnaire was used to assess subjects’ treatment satisfaction and contained 8 components and evaluates the diabetes treatment (including insulin, tablets and/or diet) in terms of convenience, flexibility and general feelings towards the treatment. The result presented is the 'Treatment Satisfaction' summary score, which is the sum of 6 of the 8 items of the DTSQs questionnaire. Response options range from 6 (best case) to 0 (worst case). Total scores for treatment satisfaction range from 0-36. Higher scores indicate higher satisfaction.
    End point type
    Secondary
    End point timeframe
    From baseline to week 56
    End point values
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Number of subjects analysed
    333
    333
    294
    Units: Units on a scale
        least squares mean (standard error)
    5.28 ± 0.23
    5.91 ± 0.23
    4.45 ± 0.24
    No statistical analyses for this end point

    Secondary: Subjects who achieve HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target (yes/no)

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    End point title
    		 Subjects who achieve HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target (yes/no)
    End point description
    Subjects who achieved HbA1c ≤6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target (yes/no) after week 56 weeks of treatment. Full analysis set (FAS=1225) included all randomised subjects who had received at least one dose of semaglutide or sitagliptin. All 1225 subjects included in the FAS contributed to this analysis.
    End point type
    Secondary
    End point timeframe
    After 56 weeks of treatment
    End point values
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Number of subjects analysed
    409
    409
    407
    Units: Subjects
        Yes
    215
    270
    83
        No
    194
    139
    324
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For AEs on-treatment period - From date of first trial product (visit 2) until date of the end of treatment follow-up visit (visit 14) or date of the last trial product dose plus 42 days (5 weeks plus the 7 days visit window), whichever comes first.
    Adverse event reporting additional description
    Safety analysis set included all subjects randomised to at least one dose of semaglutide or sitagliptin. Number of deaths causally related to treatment is the data considered to present under ‘total number of deaths resulting from adverse events’.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Semaglutide 0.5 mg + Sitagliptin placebo
    Reporting group description
    		 Semaglutide 0.5 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily.

    Reporting group title
    Semaglutide 1.0 mg + Sitagliptin placebo
    Reporting group description
    		 Semaglutide 1.0 mg administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin placebo (0 mg) administered orally once daily.

    Reporting group title
    Sitagliptin + Semaglutide placebo
    Reporting group description
    		 Subjects were randomised to 2 different placebo arms (sitagliptin + semaglutide placebo 0.5 mg and sitagliptin + semaglutide placebo 1.0 mg). Both arms were pooled together for data analysis. Semaglutide placebo administered subcutaneously (s.c., under the skin) once weekly, in the thigh, abdomen, or upper arm, at any time of day irrespective of meals. Sitagliptin (100 mg) administered orally once daily.

    Serious adverse events
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 409 (7.33%)
    30 / 409 (7.33%)
    29 / 407 (7.13%)
         number of deaths (all causes)
    2
    1
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of eyelid
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma metastatic
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Haemorrhoid operation
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus operation
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Granuloma
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Gas poisoning
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    3 / 407 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Abdominal lymphadenopathy
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Splenic lesion
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic disorder
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis necrotising
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papilla of Vater stenosis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Swollen tongue
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    2 / 409 (0.49%)
    1 / 409 (0.24%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 409 (0.00%)
    2 / 409 (0.49%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 409 (0.24%)
    2 / 409 (0.49%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Xanthelasma
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glycosuria
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ketonuria
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligamentitis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 409 (0.24%)
    1 / 409 (0.24%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 409 (0.49%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 409 (0.00%)
    0 / 409 (0.00%)
    1 / 407 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 409 (0.00%)
    1 / 409 (0.24%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    0 / 407 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 409 (0.24%)
    0 / 409 (0.00%)
    2 / 407 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Semaglutide 0.5 mg + Sitagliptin placebo Semaglutide 1.0 mg + Sitagliptin placebo Sitagliptin + Semaglutide placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    204 / 409 (49.88%)
    194 / 409 (47.43%)
    151 / 407 (37.10%)
    Investigations
    Lipase increased
         subjects affected / exposed
    33 / 409 (8.07%)
    32 / 409 (7.82%)
    29 / 407 (7.13%)
         occurrences all number
    41
    38
    33
    Nervous system disorders
    Headache
         subjects affected / exposed
    26 / 409 (6.36%)
    29 / 409 (7.09%)
    17 / 407 (4.18%)
         occurrences all number
    81
    42
    29
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    18 / 409 (4.40%)
    23 / 409 (5.62%)
    8 / 407 (1.97%)
         occurrences all number
    20
    29
    9
    Diarrhoea
         subjects affected / exposed
    53 / 409 (12.96%)
    53 / 409 (12.96%)
    29 / 407 (7.13%)
         occurrences all number
    91
    85
    35
    Dyspepsia
         subjects affected / exposed
    26 / 409 (6.36%)
    20 / 409 (4.89%)
    9 / 407 (2.21%)
         occurrences all number
    28
    27
    11
    Nausea
         subjects affected / exposed
    73 / 409 (17.85%)
    72 / 409 (17.60%)
    30 / 407 (7.37%)
         occurrences all number
    110
    140
    38
    Vomiting
         subjects affected / exposed
    33 / 409 (8.07%)
    41 / 409 (10.02%)
    11 / 407 (2.70%)
         occurrences all number
    49
    119
    16
    Infections and infestations
    Influenza
         subjects affected / exposed
    18 / 409 (4.40%)
    22 / 409 (5.38%)
    27 / 407 (6.63%)
         occurrences all number
    23
    25
    30
    Nasopharyngitis
         subjects affected / exposed
    50 / 409 (12.22%)
    29 / 409 (7.09%)
    42 / 407 (10.32%)
         occurrences all number
    63
    33
    51
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 409 (6.36%)
    27 / 409 (6.60%)
    11 / 407 (2.70%)
         occurrences all number
    28
    29
    11

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2013
    Storage condition description for sitagliptin 100 mg and sitagliptin 100 mg placebo was amended to reflect current storage conditions. Dosage of placebo was changed to 0 mg in the treatment of subjects table (5.1) to ensure alignment within the table and for further clarity.
    10 Apr 2014
    Definition of hypoglycaemia including an additional hypoglycaemia endpoint was amended to include ''severe or BG confirmed systemic hypoglycaemia". Accordingly, associated statistical analysis, trial design and population, laboratory assessments, and minor updates for general clarification were amended.

    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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