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    Clinical Trial Results:
    Efficacy and safety of oral semaglutide versus placebo in subjects with type 2 diabetes mellitus treated with diet and exercise only. A 26-week, randomised, double-blind, placebo-controlled trial.

    Summary
    EudraCT number
    		 2015-005622-19
    Trial protocol
    		 BG   CZ  
    Global end of trial date
    08 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2018
    First version publication date
    23 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9924-4233
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02906930
    WHO universal trial number (UTN)
    		 U1111-1177-5112
    Other trial identifiers
    		 Japanese trial registration: JapicCTI-163384
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of three dose levels of once-daily oral semaglutide (3, 7 and 14 mg) vs once-daily placebo on glycaemic control in subjects with type 2 diabetes treated with diet and exercise only.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013), ICH Good Clinical Practice, including archiving of essential documents (1996), and 21 CFR 312.120.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    20 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 35
    Country: Number of subjects enrolled
    Czech Republic: 28
    Country: Number of subjects enrolled
    Japan: 116
    Country: Number of subjects enrolled
    Mexico: 76
    Country: Number of subjects enrolled
    Algeria: 60
    Country: Number of subjects enrolled
    Russian Federation: 88
    Country: Number of subjects enrolled
    Serbia: 33
    Country: Number of subjects enrolled
    Turkey: 54
    Country: Number of subjects enrolled
    United States: 213
    Worldwide total number of subjects
    703
    EEA total number of subjects
    63
    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)
    560
    From 65 to 84 years
    143
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 93 sites in 9 countries as follows: Algeria (4), Bulgaria (3), Czech Republic (5), Japan (6), Mexico (2), Russian Federation (9), Serbia (3), Turkey (7), and United States: 53 sites screened/48 sites randomised subjects.

    Pre-assignment
    Screening details
    		 Not applicable

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The trial was double blinded and the clinical study group and the investigator remained blinded throughout the trial. The blinding was to be maintained until the database had been released for statistical analysis after data base lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oral semaglutide 3 mg
    Arm description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 26.
    Arm type
    		 Experimental

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

    Arm title
    		 Oral semaglutide 7 mg
    Arm description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 4 and oral semaglutide 7 mg tablets once daily from week 5 to week 26.
    Arm type
    		 Experimental

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

    Arm title
    		 Oral semaglutide 14 mg
    Arm description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 4, oral semaglutide 7 mg tablets once daily from week 5 to week 8 and oral semaglutide 14 mg tablets once daily from week 9 to week 26.
    Arm type
    		 Experimental

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

    Arm title
    		 Placebo
    Arm description
    		 Subjects were to receive placebo tablets once daily from week 0 to week 26.
    Arm type
    		 Placebo

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

    Number of subjects in period 1
    		Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Started
    175
    175
    175
    178
    Exposed
    175
    175
    175
    178
    Completed
    169
    161
    163
    170
    Not completed
    6
    14
    12
    8
         Consent withdrawn by subject
    -
    5
    5
    4
         Unclassified
    1
    2
    1
    2
         Lost to follow-up
    5
    7
    5
    2
         Died
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oral semaglutide 3 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 26.

    Reporting group title
    Oral semaglutide 7 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 4 and oral semaglutide 7 mg tablets once daily from week 5 to week 26.

    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 4, oral semaglutide 7 mg tablets once daily from week 5 to week 8 and oral semaglutide 14 mg tablets once daily from week 9 to week 26.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to receive placebo tablets once daily from week 0 to week 26.

    Reporting group values
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo Total
    Number of subjects
    		 175 175 175 178 703
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 136 135 144 145 560
        From 65-74 years
    		 33 35 29 29 126
        From 75-84 years
    		 6 5 2 4 17
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55 ( 11 ) 56 ( 11 ) 54 ( 11 ) 54 ( 11 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 86 82 89 89 346
        Male
    		 89 93 86 89 357
    Glycosylated haemoglobin (HbA1c)
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    		 7.9 ( 0.7 ) 8.0 ( 0.6 ) 8.0 ( 0.7 ) 7.9 ( 0.7 ) -
    Fasting plasma glucose
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 8.78 ( 2.35 ) 8.98 ( 2.34 ) 8.77 ( 2.17 ) 8.88 ( 2.16 ) -
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 86.9 ( 21 ) 89 ( 21.8 ) 88.1 ( 22.1 ) 88.6 ( 23.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Oral semaglutide 3 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 26.

    Reporting group title
    Oral semaglutide 7 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 4 and oral semaglutide 7 mg tablets once daily from week 5 to week 26.

    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 4, oral semaglutide 7 mg tablets once daily from week 5 to week 8 and oral semaglutide 14 mg tablets once daily from week 9 to week 26.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to receive placebo tablets once daily from week 0 to week 26.

    Primary: Change in HbA1c

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    End point title
    		 Change in HbA1c
    End point description
    Change from baseline (week 0) in HbA1c at week 26. Data from all randomised subjects in the full analysis set (FAS), irrespective of premature trial product discontinuation and initiation of rescue medication (in-trial observation period). Number of subjects analysed=number of subjects with available data.
    End point type
    Primary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    167
    160
    160
    168
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -0.9 ( 1.2 )
    -1.3 ( 1.0 )
    -1.5 ( 1.0 )
    -0.3 ( 1.2 )
    Statistical analysis title
    		 Oral semaglutide 14 mg vs. Placebo
    Statistical analysis description
    The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). Missing values were imputed by a pattern mixture model using multiple imputation. Patterns were defined by use of trial product and rescue medication. The imputation and the analysis were based on ANCOVA models. Analysis results were combined using Rubin’s rule.
    Comparison groups
    Placebo v Oral semaglutide 14 mg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Pattern mixture model
    Parameter type
    		 Estimated treatment difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 -0.9
    Notes
    [1] - A weighted Bonferroni closed testing strategy was used to control for multiplicity. Subjects in this analysis=number of subjects with available data; all subjects in the FAS (N=353) contributed with data to the analysis.
    Statistical analysis title
    		 Oral semaglutide 7 mg vs. Placebo
    Statistical analysis description
    The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). Missing values were imputed by a pattern mixture model using multiple imputation. Patterns were defined by use of trial product and rescue medication. The imputation and the analysis were based on ANCOVA models. Analysis results were combined using Rubin’s rule.
    Comparison groups
    Oral semaglutide 7 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 Pattern mixture model
    Parameter type
    		 Estimated treatment difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 -0.6
    Notes
    [2] - A weighted Bonferroni closed testing strategy was used to control for multiplicity. Subjects in this analysis=number of subjects with available data; all subjects in the FAS (N=353) contributed with data to the analysis.
    Statistical analysis title
    		 Oral semaglutide 3 mg vs. Placebo
    Statistical analysis description
    The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). Missing values were imputed by a pattern mixture model using multiple imputation. Patterns were defined by use of trial product and rescue medication. The imputation and the analysis were based on ANCOVA models. Analysis results were combined using Rubin’s rule.
    Comparison groups
    Oral semaglutide 3 mg v Placebo
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 Pattern mixture model
    Parameter type
    		 Estimated treatment difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.4
    Notes
    [3] - A weighted Bonferroni closed testing strategy was used to control for multiplicity. Subjects in this analysis=number of subjects with available data; all subjects in the FAS (N=353) contributed with data to the analysis.

    Secondary: Change in body weight (kg)

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    End point title
    		 Change in body weight (kg)
    End point description
    Change from baseline in body weight at week 26. Data from all randomised subjects in the FAS, irrespective of premature trial product discontinuation and initiation of rescue medication (in-trial observation period). Number of subjects analysed=number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    168
    160
    160
    168
    Units: kg
        arithmetic mean (standard deviation)
    -1.5 ( 3.3 )
    -2.6 ( 4.1 )
    -4.0 ( 4.2 )
    -1.4 ( 3.5 )
    Statistical analysis title
    		 Oral semaglutide 14 mg vs Placebo
    Statistical analysis description
    The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). Missing values were imputed by a pattern mixture model using multiple imputation. Patterns were defined by use of trial product and rescue medication. The imputation and the analysis were based on ANCOVA models. Analysis results were combined using Rubin’s rule.
    Comparison groups
    Oral semaglutide 14 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001
    Method
    		 Pattern mixture model
    Parameter type
    		 Estimated treatment difference
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 -1.5
    Notes
    [4] - A weighted Bonferroni closed testing strategy was used to control for multiplicity. Subjects in this analysis=number of subjects with available data; all subjects in the FAS (N=353) contributed with data to the analysis.
    Statistical analysis title
    		 Oral semaglutide 7 mg vs. Placebo
    Statistical analysis description
    The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). Missing values were imputed by a pattern mixture model using multiple imputation. Patterns were defined by use of trial product and rescue medication. The imputation and the analysis were based on ANCOVA models. Analysis results were combined using Rubin’s rule.
    Comparison groups
    Oral semaglutide 7 mg v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0866
    Method
    		 Pattern mixture model
    Parameter type
    		 Estimated treatment difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 0.1
    Notes
    [5] - A weighted Bonferroni closed testing strategy was used to control for multiplicity. Subjects in this analysis=number of subjects with available data; all subjects in the FAS (N=353) contributed with data to the analysis.
    Statistical analysis title
    		 Oral semaglutide 3 mg vs. Placebo
    Statistical analysis description
    The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). Missing values were imputed by a pattern mixture model using multiple imputation. Patterns were defined by use of trial product and rescue medication. The imputation and the analysis were based on ANCOVA models. Analysis results were combined using Rubin’s rule.
    Comparison groups
    Oral semaglutide 3 mg v Placebo
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.8692
    Method
    		 Pattern mixture model
    Parameter type
    		 Estimated treatment difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.8
    Notes
    [6] - A weighted Bonferroni closed testing strategy was used to control for multiplicity. Subjects in this analysis=number of subjects with available data; all subjects in the FAS (N=353) contributed with data to the analysis.

    Secondary: Change in fasting plasma glucose

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    End point title
    		 Change in fasting plasma glucose
    End point description
    Change from baseline (week 0) in FPG at week 26. Observed data from all randomised subjects in the FAS, irrespective of premature trial product discontinuation and initiation of rescue medication (in-trial observation period). Number of subjects analysed=number of subjects with available data
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    166
    160
    160
    166
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.89 ( 2.67 )
    -1.52 ( 2.28 )
    -1.92 ( 2.04 )
    -0.18 ( 2.37 )
    No statistical analyses for this end point

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

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    End point title
    		 HbA1c < 7.0% (53 mmol/mol) (American Diabetes Association target) (yes/no)
    End point description
    Percentage of subjects achieving HbA1c <7.0% at week 26. Observed data from all randomised subjects in the FAS, irrespective of premature trial product discontinuation and initiation of rescue medication (in-trial observation period). Number of subjects analysed=number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After week 26
    End point values
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    167
    160
    160
    168
    Units: Percentage of subjects
    number (not applicable)
        Yes
    55.1
    68.8
    76.9
    31.0
        No
    44.9
    31.3
    23.1
    69.0
    No statistical analyses for this end point

    Secondary: Number of treatment-emergent adverse events during exposure to trial product

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    End point title
    		 Number of treatment-emergent adverse events during exposure to trial product
    End point description
    An adverse event was defined as being treatment-emergent if the event had onset in the on-treatment observation period. The endpoint was assessed up to approximately 31 weeks, which is the 26-week treatment period plus the 5-week follow-up period. Results are based on the safety analysis set (SAS), which included all randomised subjects who received at least one dose of trial product (oral semaglutide or placebo).
    End point type
    Secondary
    End point timeframe
    Assessed up to approximately 31 weeks
    End point values
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    175
    175
    175
    178
    Units: Events
        number (not applicable)
    290
    258
    304
    263
    No statistical analyses for this end point

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

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    End point title
    		 Number of treatment-emergent severe or blood glucose-confirmed symptomatic hypoglycaemic episodes during exposure to trial product
    End point description
    Severe or blood glucose-confirmed symptomatic hypoglycaemia: an episode that was severe according to the American Diabetes Association (ADA) classification or confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Results are based on the SAS.
    End point type
    Secondary
    End point timeframe
    Assessed up to approximately 31 weeks
    End point values
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    175
    175
    175
    178
    Units: hypoglycaemic episodes
    5
    2
    1
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first trial product dose (Day 1) and up to approximately 31 weeks, which is the 26-week treatment period plus the 5-week follow-up period.
    Adverse event reporting additional description
    Results are based on safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Oral semaglutide 3 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 26.

    Reporting group title
    Oral semaglutide 7 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 4 and oral semaglutide 7 mg tablets once daily from week 5 to week 26.

    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 Subjects were to receive oral semaglutide 3 mg tablets once daily from week 0 to week 4, oral semaglutide 7 mg tablets once daily from week 5 to week 8 and oral semaglutide 14 mg tablets once daily from week 9 to week 26.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to receive placebo tablets once daily from week 0 to week 26.

    Serious adverse events
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 175 (2.86%)
    3 / 175 (1.71%)
    2 / 175 (1.14%)
    8 / 178 (4.49%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine tumour of the lung
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage II
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Shock
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Palatoplasty
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination, visual
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood calcitonin increased
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 175 (0.57%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroiditis subacute
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 175 (0.00%)
    1 / 175 (0.57%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 175 (0.57%)
    0 / 175 (0.00%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Oral semaglutide 3 mg Oral semaglutide 7 mg Oral semaglutide 14 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 175 (27.43%)
    37 / 175 (21.14%)
    45 / 175 (25.71%)
    26 / 178 (14.61%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 175 (3.43%)
    10 / 175 (5.71%)
    9 / 175 (5.14%)
    9 / 178 (5.06%)
         occurrences all number
    7
    16
    31
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 175 (8.57%)
    9 / 175 (5.14%)
    9 / 175 (5.14%)
    4 / 178 (2.25%)
         occurrences all number
    18
    9
    10
    4
    Nausea
         subjects affected / exposed
    14 / 175 (8.00%)
    9 / 175 (5.14%)
    28 / 175 (16.00%)
    10 / 178 (5.62%)
         occurrences all number
    17
    13
    43
    12
    Vomiting
         subjects affected / exposed
    5 / 175 (2.86%)
    8 / 175 (4.57%)
    12 / 175 (6.86%)
    4 / 178 (2.25%)
         occurrences all number
    5
    11
    15
    4
    Infections and infestations
    Influenza
         subjects affected / exposed
    9 / 175 (5.14%)
    5 / 175 (2.86%)
    4 / 175 (2.29%)
    2 / 178 (1.12%)
         occurrences all number
    9
    5
    4
    2
    Nasopharyngitis
         subjects affected / exposed
    10 / 175 (5.71%)
    11 / 175 (6.29%)
    3 / 175 (1.71%)
    6 / 178 (3.37%)
         occurrences all number
    11
    11
    4
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 175 (1.14%)
    3 / 175 (1.71%)
    9 / 175 (5.14%)
    1 / 178 (0.56%)
         occurrences all number
    2
    3
    9
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2016
    Eye examinations and additional data collection for diabetic retinopathy were introduced along with additional minor clarifications.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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