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    Clinical Trial Results:
    Efficacy and safety of oral semaglutide versus placebo in subjects with type 2 diabetes and moderate renal impairment. A 26-week randomised, double-blind, placebo-controlled trial

    Summary
    EudraCT number
    		 2015-005326-19
    Trial protocol
    		 SE   DK   FI   PL   GB  
    Global end of trial date
    15 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 May 2019
    First version publication date
    30 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9924-4234
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02827708
    WHO universal trial number (UTN)
    		 U1111-1176-9230
    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
    13 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    15 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of once daily dosing of 14 mg oral semaglutide versus placebo, both in combination with metformin and/or sulfonylurea, basal insulin alone or metformin in combination with basal insulin on glycaemic control in subjects with type 2 diabetes mellitus and moderate renal impairment.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013), ICH Good Clinical Practice, including archiving of essential documents, (1996) and 21 CFR 312.120.
    Background therapy
    		 Subjects were to continue their following listed pre-trial antidiabetic medications for the entire treatment period (week 1 - 26): metformin and/or sulphonylurea, basal insulin alone or metformin in combination with basal insulin.
    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
    Denmark: 18
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    Israel: 21
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    Russian Federation: 126
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 36
    Country: Number of subjects enrolled
    United States: 94
    Worldwide total number of subjects
    324
    EEA total number of subjects
    83
    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)
    65
    From 65 to 84 years
    251
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in 8 countries (107 sites screened/88 randomised subjects), as follows: Denmark: 7/4; Finland: 7/7; Israel: 7/6; Poland: 2/2; Russian Federation: 19/18; Sweden: 6/4; United Kingdom: 9/7; United States (US):50/40. In addition, 10 sites in the US were approved by the institutional review board, but didn’t randomise any subject

    Pre-assignment
    Screening details
    		 Not applicable.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The trial was double blinded and the clinical study group and the investigator remained blinded throughout the trial. The blinding was to be maintained until the database had been released for statistical analysis after database lock. The trial products (oral semaglutide 3, 7 and 14 mg as well as placebo) were manufactured as visually identical tablets for oral administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oral semaglutide 14 mg
    Arm description
    		 Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from week 1 to 26: 3 mg from week 1 to 4, 7 mg from week 5 to 8 and 14 mg from week 9 to 26.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Semaglutide 3 mg tablets were to be taken from week 1 to 4, once daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The trial product could be taken with up to half a glass of water (approximately 120 mL/4 fluid ounces) and was to be swallowed whole and not broken or chewed. Oral medication other than trial product could only be taken 30 minutes after administration of trial product.

    Investigational medicinal product name
    Semaglutide 7 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Semaglutide 7 mg tablets were to be taken from week 5 to 8, once daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The trial product could be taken with up to half a glass of water (approximately 120 mL/4 fluid ounces) and was to be swallowed whole and not broken or chewed. Oral medication other than trial product could only be taken 30 minutes after administration of trial product.

    Investigational medicinal product name
    Semaglutide 14 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Semaglutide 14 mg tablets were to be taken from week 9 to 26, once daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The trial product could be taken with up to half a glass of water (approximately 120 mL/4 fluid ounces) and was to be swallowed whole and not broken or chewed. Oral medication other than trial product could only be taken 30 minutes after administration of trial product.

    Arm title
    		 Placebo
    Arm description
    		 Subjects were to take oral semaglutide placebo tablets once daily from week 1 to 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
    Semaglutide placebo tablets were to be taken from week 1 – 26, once daily in the morning in a fasting state and at least 30 minutes before the first meal of the day. The trial product could be taken with up to half a glass of water (approximately 120 mL/4 fluid ounces) and was to be swallowed whole and not broken or chewed. Oral medication other than trial product could only be taken 30 minutes after administration of trial product.

    Number of subjects in period 1
    		Oral semaglutide 14 mg Placebo
    Started
    163
    161
    Completed
    158
    156
    Not completed
    5
    5
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    1
    2
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from week 1 to 26: 3 mg from week 1 to 4, 7 mg from week 5 to 8 and 14 mg from week 9 to 26.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to take oral semaglutide placebo tablets once daily from week 1 to 26.

    Reporting group values
    		 Oral semaglutide 14 mg Placebo Total
    Number of subjects
    		 163 161 324
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 26 39 65
        From 65-84 years
    		 130 121 251
        85 years and over
    		 7 1 8
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71 ( 8 ) 70 ( 8 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 80 88 168
        Male
    		 83 73 156
    Glycosylated haemoglobin (HbA1c)
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.0 ( 0.7 ) 7.9 ( 0.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from week 1 to 26: 3 mg from week 1 to 4, 7 mg from week 5 to 8 and 14 mg from week 9 to 26.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to take oral semaglutide placebo tablets once daily from week 1 to 26.

    Primary: Change in glycosylated haemoglobin (HbA1c) (In-trial observation period)

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    End point title
    		 Change in glycosylated haemoglobin (HbA1c) (In-trial observation period)
    End point description
    Change from baseline (week 0) in HbA1c was evaluated at week 26. Results are based on the in-trial observation period, which was the time period from when a subject was randomised until the final scheduled visit, including any period after initiation of rescue medication and/or premature discontinuation of trial product. Population analysed: The full analysis set (FAS), which comprised all randomised subjects. Number of subjects analysed = number of subjects with available data.
    End point type
    Primary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    154
    155
    Units: Percentage-point of HbA1c
        arithmetic mean (standard deviation)
    -1.1 ( 1.0 )
    -0.2 ( 0.9 )
    Statistical analysis title
    		 Oral semaglutide 14 mg versus Placebo
    Statistical analysis description
    The analysis was based on a pattern mixture model using multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an analysis of covariance (ANCOVA) model with treatment, region, stratification factors and the interaction between the two stratification factors as categorical fixed effects and the baseline HbA1c value as a covariate.
    Comparison groups
    Oral semaglutide 14 mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 -0.6
    Notes
    [1] - This hypothesis was controlled for multiplicity. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). Number of subjects included in analysis = Number of subjects in the FAS, who contributed to the analysis (N = 324).

    Primary: Change in glycosylated haemoglobin (HbA1c) (On-treatment without rescue medication observation period)

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    End point title
    		 Change in glycosylated haemoglobin (HbA1c) (On-treatment without rescue medication observation period)
    End point description
    Change from baseline (week 0) in HbA1c was evaluated at week 26. Results are based on the on treatment without rescue medication observation period, which was the time period when a subject was on treatment with trial product, excluding any period after initiation of rescue medication and/or premature trial product discontinuation. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Primary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    126
    127
    Units: Percentage-point of HbA1c
        arithmetic mean (standard deviation)
    -1.2 ( 0.9 )
    -0.1 ( 0.9 )
    Statistical analysis title
    		 Oral semaglutide 14 mg versus Placebo
    Statistical analysis description
    The analysis was based on a mixed model for repeated measurements (MMRM) that assumed data to be missing at random. The analysis included all scheduled post-baseline measurements up to and including week 26 as dependent variables. The independent effects were treatment, stratification factors, the interaction between the two stratification factors and region as categorical fixed effects and the baseline value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 14 mg v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Treatment difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 -0.8
    Notes
    [2] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand). Number of subjects included in analysis = Number of subjects in the FAS, who contributed to the analysis (N = 324).

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

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    End point title
    		 Change in body weight (kg) (In-trial observation period)
    End point description
    Change from baseline (week 0) in body weight was evaluated at week 26. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    154
    155
    Units: Kg
        arithmetic mean (standard deviation)
    -3.5 ( 3.8 )
    -0.9 ( 2.9 )
    Statistical analysis title
    		 Oral semaglutide 14 mg versus Placebo
    Statistical analysis description
    The analysis was based on a pattern mixture model using multiple imputation to impute missing week-26 data, assuming that such data were missing at random. The imputed data sets were analysed using an ANCOVA model with treatment, region, stratification factors and the interaction between the two stratification factors as categorical fixed effects and the baseline body weight value as a covariate.
    Comparison groups
    Oral semaglutide 14 mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 -1.8
    Notes
    [3] - This hypothesis was controlled for multiplicity. The estimated treatment effect includes the effect of any rescue medication and any effect after premature trial product discontinuation (treatment policy estimand). Number of subjects included in analysis = Number of subjects in the FAS, who contributed to the analysis (N = 323).

    Secondary: Change in body weight (kg) (On-treatment without rescue medication observation period)

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    End point title
    		 Change in body weight (kg) (On-treatment without rescue medication observation period)
    End point description
    Change from baseline (week 0) in body weight was evaluated at week 26. Results are based on the on treatment without rescue medication observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    126
    127
    Units: Kg
        arithmetic mean (standard deviation)
    -3.9 ( 3.6 )
    -0.9 ( 2.9 )
    Statistical analysis title
    		 Oral semaglutide 14 mg versus Placebo
    Statistical analysis description
    The analysis was based on a MMRM that assumed data to be missing at random. The analysis included all scheduled post-baseline measurements up to and including week 26 as dependent variables. The independent effects were treatment, stratification factors, the interaction between the two stratification factors and region as categorical fixed effects and the baseline value as a covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 14 mg v Placebo
    Number of subjects included in analysis
    253
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001
    Method
    		 MMRM
    Parameter type
    		 Treatment difference
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 -1.9
    Notes
    [4] - This hypothesis was not controlled for multiplicity. The estimated treatment effect excludes the effect of any rescue medication and any effect after premature trial product discontinuation (hypothetical estimand). Number of subjects included in analysis = Number of subjects in the FAS, who contributed to the analysis (N = 323).

    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 fasting plasma glucose (FPG) was evaluated at week 26. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 26
    End point values
    		 Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    151
    151
    Units: mmol/L
        arithmetic mean (standard deviation)
    -1.58 ( 2.96 )
    -0.34 ( 3.03 )
    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
    Subjects who achieved (yes/no) HbA1c <7.0% (American Diabetes Association (ADA) target), was evaluated at week 26. Results are based on the in-trial observation period. Population analysed: The FAS. Number of subjects analysed = number of subjects with available data.
    End point type
    Secondary
    End point timeframe
    After week 26
    End point values
    		 Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    154
    155
    Units: Subjects
        Yes
    89
    35
        No
    65
    120
    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
    Treatment emergent adverse events (TEAEs) were recorded during the exposure to trial products. Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent. On-treatment observation period: Time period when a subject was on treatment with trial product, including any period after initiation of rescue medication. Population analysed: The safety analysis set, which included all randomised subjects who received at least one dose of trial product.
    End point type
    Secondary
    End point timeframe
    Assessed up to approximately 31 weeks
    End point values
    		 Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    163
    161
    Units: Events
    463
    331
    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
    Treatment emergent severe or blood glucose-confirmed confirmed symptomatic hypoglycaemic episodes were recorded during exposure to trial products. Hypoglycaemic episodes with onset during the on-treatment observation period were considered treatment-emergent. Severe hypoglycaemia was defined as an episode requiring assistance of another person to actively administer carbohydrate or glucagon, or take other corrective actions. BG-confirmed symptomatic hypoglycaemia: Confirmed by a glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia. Population analysed: The safety analysis set.
    End point type
    Secondary
    End point timeframe
    Assessed up to approximately 31 weeks
    End point values
    		 Oral semaglutide 14 mg Placebo
    Number of subjects analysed
    163
    161
    Units: Episodes
    17
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 1 – 31 (26 weeks treatment period + 5 weeks follow-up period).
    Adverse event reporting additional description
    Results are based on the safety analysis set. All presented AEs are TEAEs which were recorded during the exposure to trial products. Adverse events (AEs) with onset during the on-treatment observation period were considered treatment-emergent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to take oral semaglutide placebo tablets once daily from week 1 to 26.

    Reporting group title
    Oral semaglutide 14 mg
    Reporting group description
    		 Subjects were to take oral semaglutide tablets once daily in a dose escalation manner from week 1 to 26: 3 mg from week 1 to 4, 7 mg from week 5 to 8 and 14 mg from week 9 to 26.

    Serious adverse events
    		 Placebo Oral semaglutide 14 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 161 (10.56%)
    17 / 163 (10.43%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 161 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina unstable
         subjects affected / exposed
    0 / 161 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dysarthria
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eyelid ptosis
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arteriosclerotic gangrene
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary sepsis
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected bite
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site abscess
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Oral semaglutide 14 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 161 (19.88%)
    75 / 163 (46.01%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 161 (4.97%)
    10 / 163 (6.13%)
         occurrences all number
    21
    13
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 161 (3.73%)
    19 / 163 (11.66%)
         occurrences all number
    6
    23
    Diarrhoea
         subjects affected / exposed
    6 / 161 (3.73%)
    17 / 163 (10.43%)
         occurrences all number
    16
    24
    Dyspepsia
         subjects affected / exposed
    2 / 161 (1.24%)
    16 / 163 (9.82%)
         occurrences all number
    2
    20
    Nausea
         subjects affected / exposed
    12 / 161 (7.45%)
    31 / 163 (19.02%)
         occurrences all number
    12
    38
    Vomiting
         subjects affected / exposed
    2 / 161 (1.24%)
    19 / 163 (11.66%)
         occurrences all number
    2
    29
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    9 / 161 (5.59%)
    1 / 163 (0.61%)
         occurrences all number
    9
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 161 (0.00%)
    11 / 163 (6.75%)
         occurrences all number
    0
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2016
    1) Additional eye examinations and fundus photography or dilated fundoscopy at end of trial and after premature discontinuation of trial product. 2) Fundoscopy requires pharmacological dilation of both pupils. 3) Eye examination category added as supportive secondary endpoint. 4) Diabetic retinopathy and related complications added as adverse events requiring additional data collection. 5) Addition of ‘Diabetic retinopathy complications’ subsection to “Benefit risk assessment of the trial” section of the protocol.

    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
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