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    Clinical Trial Results:
    Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily versus placebo in subjects with non-alcoholic steatohepatitis

    Summary
    EudraCT number
    		 2016-000685-39
    Trial protocol
    		 GB   GR   BG   FI   SE   NL   AT   BE   FR   ES   DK  
    Global end of trial date
    19 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2021
    First version publication date
    01 Apr 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9931-4296
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02970942
    WHO universal trial number (UTN)
    		 U1111-1179-7464
    Other trial identifiers
    		 Japanese registration number: 25-1634
    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
    15 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to compare the effect of semaglutide subcutaneous (s.c.) once daily versus placebo on histological resolution of non-alcoholic steatohepatitis (NASH).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Fortaleza, Brazil, 2013) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (June 1996), including archiving of essential documents, and 21 United States Code of Federal Regulations (CFR) 312.120.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 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
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Japan: 41
    Country: Number of subjects enrolled
    Russian Federation: 49
    Country: Number of subjects enrolled
    United States: 91
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 28
    Worldwide total number of subjects
    320
    EEA total number of subjects
    82
    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)
    262
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Trial was conducted at 114 sites in 16 countries (number of sites that screened subjects/randomised subjects):Australia(4/3);Austria(3/3); Belgium(4/4);Bulgaria(2/2);Canada(9/7);Denmark(2/2);Finland(1/1);France(8/6);Greece(5/5);Japan(13/12);Netherlands(7/5);Russian Federation(25/17);Spain(6/5);Sweden(3/2); United Kingdom(15/11);United States(36/29)

    Pre-assignment
    Screening details
    		 Subjects were randomised in a 3:3:3:1:1:1 ratio to receive once-daily semaglutide or placebo subcutaneously. After randomisation, the subjects entered a dose-escalation period, with increase in dose every 4 weeks until the target dose was reached.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Semaglutide 0.1 mg
    Arm description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 milligrams (mg) of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.1 mg was reached: 0.05 mg (week 1 to week 4) and 0.1 mg (week 5 to week 72).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide B 1 mg/ml NovoPen4
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.1 mg was reached: 0.05 mg (week 1 to week 4) and 0.1 mg (week 5 to week 72).

    Arm title
    		 Semaglutide 0.2 mg
    Arm description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.2 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8) and 0.2 mg (week 9 to week 72).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide B 1 mg/ml NovoPen4
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.2 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8) and 0.2 mg (week 9 to week 72).

    Arm title
    		 Semaglutide 0.4 mg
    Arm description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.4 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8), 0.2 mg (week 9 to week 12), 0.3 mg (week 13 to week 16) and 0.4 mg (week 17 to week 72).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide B 1 mg/ml NovoPen4
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.4 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8), 0.2 mg (week 9 to week 12), 0.3 mg (week 13 to week 16) and 0.4 mg (week 17 to week 72).

    Arm title
    		 Placebo
    Arm description
    		 Subjects were to receive once daily s.c. injection of placebo matched to semaglutide (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg or 0.4 mg) for 72 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Semaglutide placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive once daily s.c. injection of placebo matched to semaglutide (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg or 0.4 mg) for 72 weeks.

    Number of subjects in period 1
    		Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Started
    80
    78
    82
    80
    Completed
    76
    72
    77
    77
    Not completed
    4
    6
    5
    3
         Death
    -
    1
    -
    -
         Withdrawal by Subject
    3
    5
    3
    2
         Lost to follow-up
    1
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 0.1 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 milligrams (mg) of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.1 mg was reached: 0.05 mg (week 1 to week 4) and 0.1 mg (week 5 to week 72).

    Reporting group title
    Semaglutide 0.2 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.2 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8) and 0.2 mg (week 9 to week 72).

    Reporting group title
    Semaglutide 0.4 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.4 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8), 0.2 mg (week 9 to week 12), 0.3 mg (week 13 to week 16) and 0.4 mg (week 17 to week 72).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of placebo matched to semaglutide (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg or 0.4 mg) for 72 weeks.

    Reporting group values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo Total
    Number of subjects
    		 80 78 82 80 320
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.2 ( 10.9 ) 58.1 ( 9.9 ) 54.3 ( 10.2 ) 52.4 ( 10.8 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 51 52 47 44 194
        Male
    		 29 26 35 36 126

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 0.1 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 milligrams (mg) of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.1 mg was reached: 0.05 mg (week 1 to week 4) and 0.1 mg (week 5 to week 72).

    Reporting group title
    Semaglutide 0.2 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.2 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8) and 0.2 mg (week 9 to week 72).

    Reporting group title
    Semaglutide 0.4 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.4 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8), 0.2 mg (week 9 to week 12), 0.3 mg (week 13 to week 16) and 0.4 mg (week 17 to week 72).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of placebo matched to semaglutide (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg or 0.4 mg) for 72 weeks.

    Primary: NASH resolution without worsening of fibrosis (yes/no)

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    End point title
    		 NASH resolution without worsening of fibrosis (yes/no)
    End point description
    NASH resolution defined as lobular inflammation of 0 or 1; hepatocellular ballooning reduced to 0; both criteria were necessary conditions. Hepatocellular ballooning range 0-2; lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Worsening of fibrosis defined by an increase in fibrosis at least one stage of Kleiner fibrosis classification: fibrosis stages range 0-4, with higher scores indicating greater fibrosis (0=None,4=Cirrhosis). Full analysis set included all randomised subjects. Number of subjects analysed = Number of subjects with fibrosis stage 2 or 3 at baseline who contributed to the analysis. In below table, ‘Yes’ infers percentage of subjects who achieved NASH resolution without worsening of fibrosis and ‘No’ infers vice-versa; ‘Missing’ refers to percentage of subjects with data missing due to different reasons (lost to follow-up, withdrawal).
    End point type
    Primary
    End point timeframe
    After 72 weeks
    End point values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Number of subjects analysed
    57
    59
    56
    58
    Units: Percentage of subjects
    number (not applicable)
        Yes
    40.4
    35.6
    58.9
    17.2
        No
    54.4
    47.5
    30.4
    74.1
        Missing
    5.3
    16.9
    10.7
    8.6
    Statistical analysis title
    		 Semaglutide 0.1 mg versus Placebo
    Statistical analysis description
    The common odds ratio was estimated together with 95% confidence interval using the Mantel-Haenszel estimator associated with the Cochran-Mantel-Haenszel test.
    Comparison groups
    Semaglutide 0.1 mg v Placebo
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 t-test, 2-sided
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.29
         upper limit
    		 8.86
    Statistical analysis title
    		 Semaglutide 0.2 mg versus Placebo
    Statistical analysis description
    The common odds ratio was estimated together with 95% confidence interval using the Mantel-Haenszel estimator associated with the Cochran-Mantel-Haenszel test.
    Comparison groups
    Semaglutide 0.2 mg v Placebo
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0359
    Method
    		 t-test, 2-sided
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 7.56
    Statistical analysis title
    		 Semaglutide 0.4 mg versus Placebo
    Statistical analysis description
    The common odds ratio was estimated together with 95% confidence interval using the Mantel-Haenszel estimator associated with the Cochran-Mantel-Haenszel test.
    Comparison groups
    Semaglutide 0.4 mg v Placebo
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.6
         upper limit
    		 17.63

    Secondary: At least one stage of liver fibrosis improvement with no worsening of NASH (yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation or hepatocyte ballooning according to NASH clinical research network (CRN) criteria)

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    End point title
    		 At least one stage of liver fibrosis improvement with no worsening of NASH (yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation or hepatocyte ballooning according to NASH clinical research network (CRN) criteria)
    End point description
    Worsening of fibrosis defined by an increase in fibrosis at least one stage of Kleiner fibrosis classification: fibrosis stages range from 0-4, higher scores indicate greater fibrosis (0=None, 4=Cirrhosis). Full analysis set included all randomised subjects. Number of subjects analysed = Number of subjects with fibrosis stage 2 or 3 at baseline who contributed to the analysis. In below table, ‘Yes’ infers percentage of subjects who achieved at least one stage of fibrosis improvement with no worsening of NASH; ‘No’ infers vice-versa; ‘Missing’ refers to percentage of subjects with data missing due to different reasons (lost to follow-up, withdrawal).
    End point type
    Secondary
    End point timeframe
    After 72 weeks
    End point values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Number of subjects analysed
    57
    59
    56
    58
    Units: Percentage of subjects
    number (not applicable)
        Yes
    49.1
    32.2
    42.9
    32.8
        No
    45.6
    50.8
    46.4
    58.6
        Missing
    5.3
    16.9
    10.7
    8.6
    No statistical analyses for this end point

    Secondary: Change in non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8)

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    End point title
    		 Change in non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8)
    End point description
    Percentage of subjects who had worsened, improved or had no change in total NAS from baseline to week 72 is presented. Worsening is defined as an increase of at least 1 in the NAS; Improvement is defined as a decrease of at least 1 in the NAS; while no change corresponds to no change in NAS from baseline to week 72. NAS is calculated as the sum of scores for steatosis (0 to 3), lobular inflammation (0 to 3), and hepatocyte ballooning (0 to 2). Therefore, it is assessed on a scale of 0-8, with higher scores indicating more severe disease. The endpoint was evaluated based on the data from in-trial period which started on the date of the randomisation visit and ended on the first of the following dates (both inclusive): 1) follow-up visit (Week 79); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. Full analysis set included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From baseline to week 72
    End point values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Number of subjects analysed
    80
    78
    82
    80
    Units: Percentage of subjects
    number (not applicable)
        Improvement
    71.3
    79.5
    82.9
    43.8
        Worsening
    7.5
    2.6
    3.7
    16.3
        No change
    13.8
    5.1
    1.2
    27.5
        Missing
    7.5
    12.8
    12.2
    12.5
    No statistical analyses for this end point

    Secondary: Change in stage of fibrosis according to the Kleiner fibrosis classification (0-4)

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    End point title
    		 Change in stage of fibrosis according to the Kleiner fibrosis classification (0-4)
    End point description
    Percentage of subjects who had improved, worsened, or had no change in fibrosis stage from baseline to week 72 is presented. The degree of fibrosis is described by the Kleiner fibrosis staging system, ranging from F0 (absence of fibrosis), F1 (portal/perisinusoidal fibrosis), F2 (perisinusoidal and portal/periportal fibrosis), F3 (septal or bridging fibrosis) through F4 (cirrhosis). The endpoint was evaluated based on the data from in-trial period which started on the date of the randomisation visit and ended on the first of the following dates (both inclusive): 1) follow-up visit (Week 79); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. Full analysis set included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From baseline to week 72
    End point values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Number of subjects analysed
    80
    78
    82
    80
    Units: Percentage of subjects
    number (not applicable)
        Improvement
    46.3
    32.1
    42.7
    31.3
        Worsening
    10.0
    7.7
    4.9
    18.8
        No change
    36.3
    42.3
    36.6
    37.5
        Missing
    7.5
    17.9
    15.9
    12.5
    No statistical analyses for this end point

    Secondary: Change in activity component of steatosis-activity-fibrosis (SAF) score (0-4)

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    End point title
    		 Change in activity component of steatosis-activity-fibrosis (SAF) score (0-4)
    End point description
    Percentage of subjects who had improved, worsened, or had no change in the activity component of the SAF score from baseline to week 72 is presented. The activity component of the SAF score is defined as the unweighted sum of hepatocyte ballooning (0 to 2) and lobular inflammation (0 to 3). The definition of the lobular inflammation score is modified in this calculation so that the scores 2 and 3 on the original scale are merged to a score 2. The possible range of the sum is thus 0 to 4. For all scores, a higher value indicates a more severe state of disease. The endpoint was evaluated based on the data from in-trial period which started on the date of the randomisation visit and ended on the first of the following dates (both inclusive): 1) follow-up visit (Week 79); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. Full analysis set included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From baseline to week 72
    End point values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Number of subjects analysed
    80
    78
    82
    80
    Units: Percentage of subjects
    number (not applicable)
        Improvement
    62.5
    71.8
    72.0
    42.5
        Worsening
    7.5
    3.8
    1.2
    11.3
        No change
    22.5
    11.5
    14.6
    33.8
        Missing
    7.5
    12.8
    12.2
    12.5
    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
    Change in FPG from baseline to week 72 is presented. The endpoint was evaluated based on the data from in-trial period which started on the date of the randomisation visit and ended on the first of the following dates (both inclusive): 1) follow-up visit (Week 79); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. Full analysis set included all randomised subjects. Number of subjects analyzed = Number of subjects with type 2 diabetes who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline to week 72
    End point values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Number of subjects analysed
    45
    44
    47
    48
    Units: Millimoles per liter
        arithmetic mean (standard deviation)
    -1.39 ( 2.53 )
    -2.17 ( 1.82 )
    -2.09 ( 2.68 )
    -0.34 ( 2.72 )
    No statistical analyses for this end point

    Secondary: Change in glycosylated haemoglobin A1c (HbA1c)

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    End point title
    		 Change in glycosylated haemoglobin A1c (HbA1c)
    End point description
    Change in HbA1c from baseline to week 72 is presented. The endpoint was evaluated based on the data from in-trial period which started on the date of the randomisation visit and ended on the first of the following dates (both inclusive): 1) follow-up visit (Week 79); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. Full analysis set included all randomised subjects. Number of subjects analyzed = Number of subjects with type 2 diabetes who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline to week 72
    End point values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Number of subjects analysed
    46
    45
    47
    47
    Units: Percentage point of HbA1c
        arithmetic mean (standard deviation)
    -0.7 ( 1.1 )
    -1.2 ( 0.9 )
    -1.2 ( 1.0 )
    -0.0 ( 1.0 )
    No statistical analyses for this end point

    Secondary: Change in serum enhanced liver fibrosis (ELF)

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    End point title
    		 Change in serum enhanced liver fibrosis (ELF)
    End point description
    Change in ELF from baseline to week 72 is presented. The endpoint was evaluated based on the data from in-trial period which started on the date of the randomisation visit and ended on the first of the following dates (both inclusive): 1) follow-up visit (Week 79); 2) withdrawal of consent; 3) last contact with subject (for subjects lost to follow-up); 4) death. Full analysis set included all randomised subjects. Number of subjects analyzed = Number of subjects who contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline to week 72
    End point values
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Number of subjects analysed
    76
    70
    76
    75
    Units: Change in ELF score
        arithmetic mean (standard deviation)
    -0.4 ( 0.7 )
    -0.4 ( 0.8 )
    -0.6 ( 0.8 )
    0.1 ( 0.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From week 0 to week 79 Results are based on safety analysis set which included all subjects who received at least one dose of randomised treatment. All adverse events reported here are treatment emergent adverse events (TEAEs).
    Adverse event reporting additional description
    TEAE was defined as an event that had onset date during on-treatment period (for AEs), which started from date of first administration of trial product and ended on date of whatever came first: 1) last dose of trial product + 49 days (7 half lives of semaglutide); 2) end of the in-trial period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Semaglutide 0.1 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.1 mg was reached: 0.05 mg (week 1 to week 4) and 0.1 mg (week 5 to week 72).

    Reporting group title
    Semaglutide 0.2 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.2 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8) and 0.2 mg (week 9 to week 72).

    Reporting group title
    Semaglutide 0.4 mg
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of semaglutide for 72 weeks. Subjects initially received 0.05 mg of semaglutide and the dose was then escalated once in 4 weeks until the target dose of 0.4 mg was reached: 0.05 mg (week 1 to week 4), 0.1 mg (week 5 to week 8), 0.2 mg (week 9 to week 12), 0.3 mg (week 13 to week 16) and 0.4 mg (week 17 to week 72).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects were to receive once daily s.c. injection of placebo matched to semaglutide (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg or 0.4 mg) for 72 weeks.

    Serious adverse events
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 80 (15.00%)
    15 / 78 (19.23%)
    12 / 81 (14.81%)
    8 / 80 (10.00%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholesteatoma
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Neurilemmoma benign
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Peripheral T-cell lymphoma unspecified
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         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
    Sudden death
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Reproductive system and breast disorders
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Ovarian cyst
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Uterine polyp
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Atelectasis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Pleural effusion
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Major depression
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Suicidal ideation
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         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
    Post procedural haematoma
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Ventricular tachycardia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         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
    Nervous system disorders
    Diabetic neuropathy
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Epilepsy
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Transient epileptic amnesia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Colitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Colitis ischaemic
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Constipation
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Megacolon
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Nausea
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 78 (2.56%)
    0 / 81 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         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
    Endocrine disorders
    Basedow's disease
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Back pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         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
    Foot deformity
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Musculoskeletal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Anal abscess
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Cellulitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Cystitis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Cystitis escherichia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Diverticulitis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Hepatitis E
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         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
    Pneumonia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    0 / 80 (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
    Sepsis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Urosepsis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (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
    Metabolism and nutrition disorders
    Diabetic metabolic decompensation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         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
    Hyperglycaemia
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    0 / 81 (0.00%)
    0 / 80 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Semaglutide 0.1 mg Semaglutide 0.2 mg Semaglutide 0.4 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 80 (76.25%)
    64 / 78 (82.05%)
    63 / 81 (77.78%)
    55 / 80 (68.75%)
    Investigations
    Lipase increased
         subjects affected / exposed
    4 / 80 (5.00%)
    7 / 78 (8.97%)
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences all number
    5
    8
    3
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    6 / 80 (7.50%)
    2 / 78 (2.56%)
    2 / 81 (2.47%)
    2 / 80 (2.50%)
         occurrences all number
    7
    2
    2
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 80 (3.75%)
    3 / 78 (3.85%)
    3 / 81 (3.70%)
    4 / 80 (5.00%)
         occurrences all number
    3
    3
    3
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 80 (7.50%)
    6 / 78 (7.69%)
    8 / 81 (9.88%)
    6 / 80 (7.50%)
         occurrences all number
    8
    8
    10
    7
    Headache
         subjects affected / exposed
    7 / 80 (8.75%)
    10 / 78 (12.82%)
    10 / 81 (12.35%)
    8 / 80 (10.00%)
         occurrences all number
    11
    13
    13
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 80 (8.75%)
    8 / 78 (10.26%)
    7 / 81 (8.64%)
    7 / 80 (8.75%)
         occurrences all number
    7
    8
    8
    7
    Injection site bruising
         subjects affected / exposed
    1 / 80 (1.25%)
    5 / 78 (6.41%)
    3 / 81 (3.70%)
    2 / 80 (2.50%)
         occurrences all number
    1
    10
    4
    2
    Pyrexia
         subjects affected / exposed
    1 / 80 (1.25%)
    4 / 78 (5.13%)
    1 / 81 (1.23%)
    1 / 80 (1.25%)
         occurrences all number
    1
    4
    1
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 80 (1.25%)
    8 / 78 (10.26%)
    4 / 81 (4.94%)
    4 / 80 (5.00%)
         occurrences all number
    1
    9
    7
    5
    Abdominal pain
         subjects affected / exposed
    9 / 80 (11.25%)
    8 / 78 (10.26%)
    6 / 81 (7.41%)
    3 / 80 (3.75%)
         occurrences all number
    10
    9
    7
    4
    Abdominal pain upper
         subjects affected / exposed
    5 / 80 (6.25%)
    6 / 78 (7.69%)
    8 / 81 (9.88%)
    3 / 80 (3.75%)
         occurrences all number
    5
    7
    10
    4
    Constipation
         subjects affected / exposed
    12 / 80 (15.00%)
    17 / 78 (21.79%)
    18 / 81 (22.22%)
    10 / 80 (12.50%)
         occurrences all number
    14
    22
    20
    11
    Diarrhoea
         subjects affected / exposed
    23 / 80 (28.75%)
    22 / 78 (28.21%)
    16 / 81 (19.75%)
    11 / 80 (13.75%)
         occurrences all number
    31
    30
    21
    16
    Dyspepsia
         subjects affected / exposed
    4 / 80 (5.00%)
    9 / 78 (11.54%)
    4 / 81 (4.94%)
    5 / 80 (6.25%)
         occurrences all number
    4
    11
    5
    7
    Eructation
         subjects affected / exposed
    5 / 80 (6.25%)
    6 / 78 (7.69%)
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences all number
    6
    6
    1
    0
    Flatulence
         subjects affected / exposed
    2 / 80 (2.50%)
    5 / 78 (6.41%)
    3 / 81 (3.70%)
    0 / 80 (0.00%)
         occurrences all number
    2
    5
    3
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 78 (5.13%)
    5 / 81 (6.17%)
    2 / 80 (2.50%)
         occurrences all number
    3
    5
    6
    2
    Large intestine polyp
         subjects affected / exposed
    1 / 80 (1.25%)
    4 / 78 (5.13%)
    3 / 81 (3.70%)
    0 / 80 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Nausea
         subjects affected / exposed
    24 / 80 (30.00%)
    29 / 78 (37.18%)
    33 / 81 (40.74%)
    9 / 80 (11.25%)
         occurrences all number
    32
    39
    49
    10
    Vomiting
         subjects affected / exposed
    14 / 80 (17.50%)
    17 / 78 (21.79%)
    12 / 81 (14.81%)
    2 / 80 (2.50%)
         occurrences all number
    21
    26
    29
    3
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 78 (0.00%)
    1 / 81 (1.23%)
    4 / 80 (5.00%)
         occurrences all number
    1
    0
    1
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 78 (1.28%)
    4 / 81 (4.94%)
    5 / 80 (6.25%)
         occurrences all number
    1
    1
    5
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 80 (0.00%)
    4 / 78 (5.13%)
    8 / 81 (9.88%)
    7 / 80 (8.75%)
         occurrences all number
    0
    4
    8
    7
    Back pain
         subjects affected / exposed
    7 / 80 (8.75%)
    5 / 78 (6.41%)
    10 / 81 (12.35%)
    6 / 80 (7.50%)
         occurrences all number
    10
    5
    10
    6
    Muscle spasms
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 78 (1.28%)
    3 / 81 (3.70%)
    4 / 80 (5.00%)
         occurrences all number
    1
    1
    3
    4
    Pain in extremity
         subjects affected / exposed
    1 / 80 (1.25%)
    1 / 78 (1.28%)
    2 / 81 (2.47%)
    5 / 80 (6.25%)
         occurrences all number
    1
    1
    2
    7
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 78 (2.56%)
    1 / 81 (1.23%)
    2 / 80 (2.50%)
         occurrences all number
    4
    2
    1
    2
    Influenza
         subjects affected / exposed
    7 / 80 (8.75%)
    1 / 78 (1.28%)
    3 / 81 (3.70%)
    6 / 80 (7.50%)
         occurrences all number
    7
    1
    4
    6
    Nasopharyngitis
         subjects affected / exposed
    11 / 80 (13.75%)
    15 / 78 (19.23%)
    10 / 81 (12.35%)
    12 / 80 (15.00%)
         occurrences all number
    15
    21
    11
    22
    Sinusitis
         subjects affected / exposed
    4 / 80 (5.00%)
    7 / 78 (8.97%)
    2 / 81 (2.47%)
    1 / 80 (1.25%)
         occurrences all number
    4
    8
    4
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 80 (5.00%)
    6 / 78 (7.69%)
    3 / 81 (3.70%)
    5 / 80 (6.25%)
         occurrences all number
    4
    8
    4
    6
    Urinary tract infection
         subjects affected / exposed
    5 / 80 (6.25%)
    2 / 78 (2.56%)
    7 / 81 (8.64%)
    0 / 80 (0.00%)
         occurrences all number
    7
    2
    9
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    16 / 80 (20.00%)
    18 / 78 (23.08%)
    18 / 81 (22.22%)
    4 / 80 (5.00%)
         occurrences all number
    18
    18
    22
    4
    Diabetes mellitus
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 78 (1.28%)
    0 / 81 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    1
    0
    5
    Hyperglycaemia
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 78 (2.56%)
    3 / 81 (3.70%)
    7 / 80 (8.75%)
         occurrences all number
    1
    3
    6
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Sep 2016
    The following changes were made as per this amendment: -Clarification of process for handling increased levels of liver blood parameters -Clarification that exclusion criterion 20 (retinopathy) is only applicable to subjects with type 2 diabetes (T2D) -Additional section added: Fundoscopy/fundus photography -Exclusion criterion for severe renal impairment (estimated glomerular filtration rate (eGFR) < 30 milliliter per minute per meter square (mL/min/m2)) added, and continuous eGFR measurements during the trial
    29 Dec 2016
    The following changes were made as per this amendment: -Subjects developing T2D during the trial can be treated with antidiabetic medication -Exclusion criterion 8 updated: vitamin E and pioglitazone treatment must be stable for 90 days prior to screening/baseline liver biopsy -Statistical section updated: supportive analysis of the primary endpoint without pooling the placebo arms added. A sensitivity analysis of the primary endpoint where vitamin E use is included as a factor in the model, and a subgroup analysis for subjects who use vitamin E versus subjects who do not use vitamin E, added -Collection of daily dose for treatment with vitamin E and pioglitazone included -Text regarding new identified risk (retinopathy) included in risk/benefit section
    26 May 2017
    The following changes were made as per this amendment: -Changes to eligibility criteria implemented: Inclusion criteria 1 and 5, exclusion criteria 5, 6, 10, and 15 amended; Exclusion criteria 12 and 16 deleted -As a consequence of amending exclusion criterion 10 a new section with guidance on treatment of subjects with poorly controlled glycaemia included -Optional pre-screening included (blood samples and imaging (not involving radiation)) -Footnote to primary endpoint updated to clarify definition of resolution of NASH -Screen failure rate updated to 65% -Restrictions on bolus insulin treatment removed and short-term systemic use (less than or equal to (≤) 14 days) of corticosteroids allowed -Visit 10 must be attended in a fasting state (for calcitonin measurement)
    02 Oct 2017
    The following changes were made as per this amendment: -Global sample size reduction: from 372 to 288 randomised subjects -Expected time for planned duration of recruitment period increased from 78 to 103 weeks -Inclusion of subjects with fibrosis stage 1 (inclusion criterion 7 has been updated) -Re-test of INR allowed (if screening albumin is within central laboratory reference range) -Rephrased exclusion criterion 9 regarding treatment with drugs with potential effect on steatosis

    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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