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    Clinical Trial Results:
    Efficacy and safety of semaglutide once-weekly versus placebo as add-on to basal insulin alone or basal insulin in combination with metformin in subjects with type 2 diabetes

    Summary
    EudraCT number
    		 2013-004502-26
    Trial protocol
    		 DE   SK  
    Global end of trial date
    21 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Dec 2016
    First version publication date
    03 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9535-3627
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02305381
    WHO universal trial number (UTN)
    		 U1111-1149-3738
    Other trial identifiers
    		 Japanese trial registration: JapicCTI-142729
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    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
    29 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to demonstrate superiority of once-weekly dosing of two dose levels (0.5 mg and 1.0 mg) of semaglutide versus placebo on glycaemic control in subjects with type 2 diabetes (T2D) on basal insulin.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, ICH Good Clinical Practice, EN ISO 14155 Part 1 and 2 and FDA 21 CFR 312.120.
    Background therapy
    		 Subjects were to continue pre-trial background medication throughout the entire trial. Basal insulin with or without metformin were considered background medication.
    Evidence for comparator
    		 Not applicble
    Actual start date of recruitment
    01 Dec 2014
    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
    Germany: 70
    Country: Number of subjects enrolled
    Japan: 61
    Country: Number of subjects enrolled
    Serbia: 45
    Country: Number of subjects enrolled
    Slovakia: 40
    Country: Number of subjects enrolled
    United States: 180
    Worldwide total number of subjects
    396
    EEA total number of subjects
    110
    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)
    281
    From 65 to 84 years
    114
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 90 sites in 5 countries, as follows: Germany: 10 sites; Japan: 6 sites; Serbia: 4 sites; Slovakia: 5 sites; United States: 65.

    Pre-assignment
    Screening details
    		 Not applicable

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject
    Blinding implementation details
    Semaglutide and placebo were supplied in similar 1.5 mL pre-filled PDS290 pen-injector and were by all means visually identical and were packed and labelled to fulfil the requirements for double-blind procedures. Furthermore, equal volumes of semaglutide and placebo were administered during treatment ensuring blinding within dose-level.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Semaglutide 0.5 mg
    Arm description
    		 Subjects received semaglutide 0.25 mg subcutaneous (sc) injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to Week 30.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.

    Arm title
    		 Semaglutide 1.0 mg
    Arm description
    		 Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Semaglutide injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo injection was administered in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same day of the week during the trial.

    Number of subjects in period 1
    		Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Started
    132
    131
    133
    Premature discontinuation of treatment
    14 [1]
    16 [2]
    13 [3]
    Completed
    127
    127
    126
    Not completed
    5
    4
    7
         Not completed
    5
    4
    7
    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
    Reporting group description
    		 Subjects received semaglutide 0.25 mg subcutaneous (sc) injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to Week 30.

    Reporting group title
    Semaglutide 1.0 mg
    Reporting group description
    		 Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks.

    Reporting group values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo Total
    Number of subjects
    		 132 131 133 396
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 93 102 86 281
        From 65-84 years
    		 39 29 46 114
        85 years and over
    		 0 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.1 ( 10.3 ) 58.5 ( 9 ) 58.8 ( 10.9 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 58 54 62 174
        Male
    		 74 77 71 222
    Glycosylated haemoglobin
    Units: percentage of glycosylated haemoglobin
        arithmetic mean (standard deviation)
    		 8.36 ( 0.83 ) 8.31 ( 0.82 ) 8.42 ( 0.88 ) -
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 92.74 ( 19.57 ) 92.49 ( 22.23 ) 89.88 ( 21.06 ) -
    Fasting plasma glucose
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 161 ( 62.38 ) 152.5 ( 50.91 ) 154.1 ( 46.66 ) -
    Insulin Dose
    Number of subjects analysed for this parameter=131, 131 and 133
    Units: international unit
        median (full range (min-max))
    		 35 (15 to 300) 36 (14 to 320) 36 (12 to 124) -
    Diastolic Blood Pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 78.89 ( 9.72 ) 78.73 ( 9.98 ) 79.35 ( 9.71 ) -
    Systolic Blood Pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 134.87 ( 15 ) 134.4 ( 16.32 ) 134.99 ( 16.68 ) -
    Diabetes Treatment Satisfaction Questionnaire
    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.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 28.86 ( 6.35 ) 28.62 ( 6.45 ) 27.54 ( 6.55 ) -

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 0.5 mg
    Reporting group description
    		 Subjects received semaglutide 0.25 mg subcutaneous (sc) injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to Week 30.

    Reporting group title
    Semaglutide 1.0 mg
    Reporting group description
    		 Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks.

    Primary: Change in HbA1c

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    End point title
    		 Change in HbA1c
    End point description
    Estimated mean change from baseline in HbA1c at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements. Analysis was performed on full analysis set which included all randomised subjects who had received at least 1 dose of randomised semaglutide or placebo.
    End point type
    Primary
    End point timeframe
    From baseline to week 30
    End point values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    132
    131
    133
    Units: percentage of glycosylated hemoglobin
        least squares mean (standard error)
    -1.45 ( 0.09 )
    -1.85 ( 0.09 )
    -0.09 ( 0.09 )
    Statistical analysis title
    		 Analysis 1: Semaglutide 1.0 mg vs Placebo
    Statistical analysis description
    Hierarchical testing was performed as per sequence listed below:Change in HbA1c: semaglutide 1.0 mg vs placebo. Change in HbA1c: semaglutide 0.5 mg vs placebo. Change in body weight: semaglutide 1.0 mg vs placebo. Change in body weight: semaglutide 0.5 mg vs placebo. Analysis was performed using MMRM with treatment, country and stratification variable (HbA1c at screening [≤8.0% or >8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate
    Comparison groups
    Semaglutide 1.0 mg v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.01
         upper limit
    		 -1.5
    Notes
    [1] - Superiority for change in HbA1c was claimed if the upper limit of the 2-sided 95% CI for the estimated difference was below 0%
    Statistical analysis title
    		 Analysis 2: Semaglutide 1.0 mg vs Placebo
    Statistical analysis description
    Hierarchical testing was performed as per sequence listed below:Change in HbA1c: semaglutide 1.0 mg vs placebo. Change in HbA1c: semaglutide 0.5 mg vs placebo. Change in body weight: semaglutide 1.0 mg vs placebo. Change in body weight: semaglutide 0.5 mg vs placebo. Analysis was performed using MMRM with treatment, country and stratification variable (HbA1c at screening [≤8.0% or >8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate
    Comparison groups
    Semaglutide 0.5 mg v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 -1.1
    Notes
    [2] - Superiority for change in HbA1c was claimed if the upper limit of the 2-sided 95% CI for the estimated difference was below 0%.

    Secondary: Change in body weight

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    End point title
    		 Change in body weight
    End point description
    Estimated mean change from baseline in HbA1c at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements. Analysis was performed on full analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    132
    131
    133
    Units: kg
        least squares mean (standard error)
    -3.67 ( 0.36 )
    -6.42 ( 0.36 )
    -1.36 ( 0.37 )
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose (FPG)

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    End point title
    		 Change in fasting plasma glucose (FPG)
    End point description
    Estimated mean change from baseline in FPG at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements. Estimated mean change from baseline in FPG at week 30. Analysis was performed on full analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    132
    131
    133
    Units: mg/dL
        least squares mean (standard error)
    -29.14 ( 3.74 )
    -42.38 ( 3.76 )
    -8.51 ( 4.02 )
    No statistical analyses for this end point

    Secondary: Change in insulin dose

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    End point title
    		 Change in insulin dose
    End point description
    Estimated mean change from baseline in insulin dose at week 30 was measured in terms of ratio to baseline. Responses at week 30 are analysed using an Analysis of covariance model with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward. Analysis was performed on full analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    132
    131
    133
    Units: ratio
        least squares mean (standard error)
    0.9 ( 0.01 )
    0.85 ( 0.01 )
    0.96 ( 0.01 )
    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
    Estimated mean change from baseline in systolic and diastolic blood pressure at week 30. The post-baseline responses are analysed using a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using mixed model for repeated measurements. Analysis was performed on full analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    132
    131
    133
    Units: mm Hg
    least squares mean (standard error)
        Diastolic blood pressure
    -1.84 ( 0.73 )
    -1.5 ( 0.74 )
    -2.17 ( 0.79 )
        Systolic blood pressure
    -4.29 ( 1.26 )
    -7.27 ( 1.27 )
    -0.99 ( 1.34 )
    No statistical analyses for this end point

    Secondary: Change in patient reported outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ)

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    End point title
    		 Change in patient reported outcomes, Diabetes Treatment Satisfaction Questionnaire (DTSQ)
    End point description
    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. The post-baseline responses are analysed using an ANCOVA model with treatment, country and stratification variables (HbA1c level at screening [<= 8.0% or > 8.0%] and use of metformin [yes or no]) as fixed factors and baseline value as covariate. Mean estimates are adjusted according to observed baseline distribution. Missing data was imputed using last observation carried forward. Analysis was performed on full analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline to week 30
    End point values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    132
    131
    133
    Units: Scores on a scale
        least squares mean (standard error)
    2.73 ( 0.46 )
    3.47 ( 0.46 )
    1.25 ( 0.5 )
    No statistical analyses for this end point

    Secondary: HbA1c below 7.0% (53 mmol/mol) American Diabetes Association (ADA) target

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    End point title
    		 HbA1c below 7.0% (53 mmol/mol) American Diabetes Association (ADA) target
    End point description
    Percentage of subjects with HbA1C below 7.0% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Analysis was performed on full analysis set.
    End point type
    Secondary
    End point timeframe
    After 30 weeks treatment
    End point values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    132
    131
    133
    Units: percentage of subjects
        number (not applicable)
    60.6
    78.6
    10.5
    No statistical analyses for this end point

    Secondary: HbA1c below or equal to 6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target

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    End point title
    		 HbA1c below or equal to 6.5% (48 mmol/mol) American Association of Clinical Endocrinologists (AACE) target
    End point description
    Percentage of subjects with HbA1C below 7.0% after 30 weeks treatment. Missing data imputed from a mixed model for repeated measurements with treatment, country and stratification variable (HbA1c level at screening [<= 8.0% or > 8.0%] crossed with use of metformin [yes or no]; 2 by 2 levels) as fixed factors and baseline value as covariate, all nested within visit. Analysis was performed on full analysis set.
    End point type
    Secondary
    End point timeframe
    After 30 weeks of treatment
    End point values
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Number of subjects analysed
    132
    131
    133
    Units: percentage of participants
        number (not applicable)
    40.9
    61.1
    4.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of trial product until the end of the post-treatment follow-up period.The follow-up visit was scheduled to take place 5 weeks after the date of last dose of trial product with a visit window of +7 days (maximum 36 weeks).
    Adverse event reporting additional description
    A treatment-emergent adverse event (TEAE) was defined as an AE that had onset date (or increased in severity) during the ‘on-treatment’ observation period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Semaglutide 0.5 mg
    Reporting group description
    		 Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly up to Week 30.

    Reporting group title
    Semaglutide 1.0 mg
    Reporting group description
    		 Subjects received semaglutide 0.25 mg sc injection once weekly for 4 weeks followed by semaglutide 0.5 mg once weekly for next 4 weeks and then semaglutide 1.0 mg once weekly up to week 30.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo (matched to semaglutide) sc injection once weekly for 30 weeks.

    Serious adverse events
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 132 (6.06%)
    12 / 131 (9.16%)
    9 / 133 (6.77%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Femoral artery occlusion
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Carotid endarterectomy
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Coronary arterial stent insertion
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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
    Coronary artery bypass
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery angioplasty
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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 artery stent insertion
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Pyrexia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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
    Weight decreased
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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 disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Ischaemic stroke
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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 and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Spondylolisthesis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Diverticulitis
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Pyelonephritis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         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 / 132 (0.76%)
    0 / 131 (0.00%)
    0 / 133 (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
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 131 (0.00%)
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 131 (0.76%)
    0 / 133 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 132 (39.39%)
    54 / 131 (41.22%)
    34 / 133 (25.56%)
    Investigations
    Lipase increased
         subjects affected / exposed
    12 / 132 (9.09%)
    7 / 131 (5.34%)
    4 / 133 (3.01%)
         occurrences all number
    15
    7
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 132 (4.55%)
    9 / 131 (6.87%)
    2 / 133 (1.50%)
         occurrences all number
    6
    9
    2
    Nausea
         subjects affected / exposed
    15 / 132 (11.36%)
    22 / 131 (16.79%)
    6 / 133 (4.51%)
         occurrences all number
    21
    23
    6
    Vomiting
         subjects affected / exposed
    8 / 132 (6.06%)
    15 / 131 (11.45%)
    4 / 133 (3.01%)
         occurrences all number
    9
    17
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 132 (8.33%)
    6 / 131 (4.58%)
    14 / 133 (10.53%)
         occurrences all number
    14
    6
    16
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 132 (6.06%)
    1 / 131 (0.76%)
    4 / 133 (3.01%)
         occurrences all number
    10
    1
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 132 (1.52%)
    4 / 131 (3.05%)
    8 / 133 (6.02%)
         occurrences all number
    3
    5
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 132 (3.79%)
    7 / 131 (5.34%)
    1 / 133 (0.75%)
         occurrences all number
    5
    7
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jan 2015
    Change and clarify the wording of "Rescue criteria".

    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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