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    Clinical Trial Results:
    Efficacy and safety of oral semaglutide 25 mg once daily in adults with overweight or obesity (OASIS 4)

    Summary
    EudraCT number
    		 2021-006534-40
    Trial protocol
    		 PL  
    Global end of trial date
    07 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 May 2025
    First version publication date
    10 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9932-4954
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05564117
    WHO universal trial number (UTN)
    		 U1111-1271-9056
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Alle, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Office (2834), 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
    18 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm superior efficacy on body weight reduction from baseline (week 0) to end of treatment (week 64) of oral semaglutide 25 mg once daily versus placebo as an adjunct to reduced-calorie diet and increased physical activity in adults with overweight or obesity.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice, including archiving of essential documents. The submitted information, reflecting the data available at the data cut-off date for this report, is confirmed to be accurate.
    Background therapy
    		 -
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    11 Oct 2022
    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
    Canada: 32
    Country: Number of subjects enrolled
    Germany: 81
    Country: Number of subjects enrolled
    Poland: 80
    Country: Number of subjects enrolled
    United States: 114
    Worldwide total number of subjects
    307
    EEA total number of subjects
    161
    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)
    278
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 22 sites in 4 countries.

    Pre-assignment
    Screening details
    		 Subjects were randomised in 2:1 ratio to receive 25 milligram (mg) oral semaglutide or semaglutide matching placebo once weekly.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oral semaglutide 25 mg
    Arm description
    		 Subjects received oral semaglutide tablets once daily in a dose escalation manner for 64 weeks: 3 mg (weeks 0 to 4), 7 mg (weeks 5 to 8), 14 mg (weeks 9 to 12), and 25 mg (weeks 13 to 64).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide C
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral semaglutide tablets were administered once daily for 64 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo tablets matched to oral semaglutide once daily for 64 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets matching oral semaglutide were administered once daily for 64 weeks.

    Number of subjects in period 1
    		Oral semaglutide 25 mg Placebo
    Started
    205
    102
    Full Analysis Set (FAS)
    205
    102
    Safety Analysis Set (SAS)
    204
    102
    Completed
    196
    94
    Not completed
    9
    8
         Physician decision
    1
    -
         Consent withdrawn by subject
    1
    1
         Lost to follow-up
    7
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oral semaglutide 25 mg
    Reporting group description
    		 Subjects received oral semaglutide tablets once daily in a dose escalation manner for 64 weeks: 3 mg (weeks 0 to 4), 7 mg (weeks 5 to 8), 14 mg (weeks 9 to 12), and 25 mg (weeks 13 to 64).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo tablets matched to oral semaglutide once daily for 64 weeks.

    Reporting group values
    		 Oral semaglutide 25 mg Placebo Total
    Number of subjects
    		 205 102 307
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 184 94 278
        From 65-84 years
    		 21 8 29
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48 ( 13 ) 47 ( 13 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 155 87 242
        Male
    		 50 15 65
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 1 1 2
        Black or African American
    		 13 9 22
        White
    		 190 91 281
        Other
    		 1 1 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 17 7 24
        Not Hispanic or Latino
    		 188 95 283

    End points

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    End points reporting groups
    Reporting group title
    Oral semaglutide 25 mg
    Reporting group description
    		 Subjects received oral semaglutide tablets once daily in a dose escalation manner for 64 weeks: 3 mg (weeks 0 to 4), 7 mg (weeks 5 to 8), 14 mg (weeks 9 to 12), and 25 mg (weeks 13 to 64).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo tablets matched to oral semaglutide once daily for 64 weeks.

    Primary: Relative change in body weight

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    End point title
    		 Relative change in body weight
    End point description
    Relative change in body weight from baseline (week 0) to end of treatment (week 64) is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Primary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    192
    90
    Units: Percentage (%) point of body weight
        arithmetic mean (standard deviation)
    -14.4 ( 10.5 )
    -2.5 ( 7.9 )
    Statistical analysis title
    		 Hypothetical estimand
    Statistical analysis description
    All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 25 mg v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -13.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.53
         upper limit
    		 -11.21
    Notes
    [1] - Hypothetical estimand: Total number of subjects included in statistical analysis is 168. The number given here is auto-calculated by the system.
    Statistical analysis title
    		 Treatment policy estimand
    Statistical analysis description
    Week 64 responses were analysed using an analysis of covariance model with randomised treatment as factor and baseline body weight as covariate.
    Comparison groups
    Placebo v Oral semaglutide 25 mg
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -11.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.88
         upper limit
    		 -8.98

    Primary: Achievement of body weight reduction ≥ 5 percentage (%) (Yes/No)

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    End point title
    		 Achievement of body weight reduction ≥ 5 percentage (%) (Yes/No)
    End point description
    Achievement of body weight reduction ≥ 5% (Yes/No) at end of treatment (week 64) is presented. In the reported data, 'Yes' infers the number of participants who have achieved ≥ 5% weight loss, whereas 'No' infers the number of participants who have not achieved ≥ 5% weight loss. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Primary
    End point timeframe
    At end-of-treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    192
    90
    Units: Subjects
        Yes
    152
    28
        No
    40
    62
    Statistical analysis title
    		 Hypothetical estimand
    Statistical analysis description
    All responses prior to first discontinuation of treatment (or initiation of other anti-obesity medication or bariatric surgery) were included in a mixed model for repeated measurements with randomised treatment as factor and baseline body weight as covariate, all nested within visit.
    Comparison groups
    Oral semaglutide 25 mg v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment odds ratio
    Point estimate
    25.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.24
         upper limit
    		 48.07
    Notes
    [2] - Hypothetical estimand: Total number of subjects included in statistical analysis is 168. The number given here is auto-calculated by the system.
    Statistical analysis title
    		 Treatment policy estimand
    Statistical analysis description
    Week 64 responses were analysed using a binary logistic regression model with randomised treatment as factor and baseline body weight as covariate.
    Comparison groups
    Oral semaglutide 25 mg v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Treatment odds ratio
    Point estimate
    7.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.22
         upper limit
    		 12.76

    Secondary: Achievement of body weight reduction ≥ 10% (Yes/No)

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    End point title
    		 Achievement of body weight reduction ≥ 10% (Yes/No)
    End point description
    Achievement of body weight reduction ≥ 10% (Yes/No) at end of treatment (week 64) is presented. In the reported data, 'Yes' infers the number of participants who have achieved ≥ 10% weight loss, whereas 'No' infers the number of participants who have not achieved ≥ 10% weight loss. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    At end-of-treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    192
    90
    Units: Subjects
        Yes
    121
    13
        No
    71
    77
    No statistical analyses for this end point

    Secondary: Achievement of body weight reduction ≥ 15% (Yes/No)

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    End point title
    		 Achievement of body weight reduction ≥ 15% (Yes/No)
    End point description
    Achievement of body weight reduction ≥ 15% (Yes/No) at end of treatment (week 64) is presented. In the reported data, 'Yes' infers the number of participants who have achieved ≥ 15% weight loss, whereas 'No' infers the number of participants who have not achieved ≥ 15% weight loss. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    At end-of-treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    192
    90
    Units: Subjects
        Yes
    96
    5
        No
    96
    85
    No statistical analyses for this end point

    Secondary: Achievement of body weight reduction ≥ 20% (Yes/No)

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    End point title
    		 Achievement of body weight reduction ≥ 20% (Yes/No)
    End point description
    Achievement of body weight reduction ≥ 20% (Yes/No) at end of treatment (week 64) is presented. In the reported data, 'Yes' infers the number of participants who have achieved ≥ 20% weight loss, whereas 'No' infers the number of participants who have not achieved ≥ 20% weight loss. The end point was evaluated based on the data from in-trial period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    At end-of-treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    192
    90
    Units: Subjects
        Yes
    57
    3
        No
    135
    87
    No statistical analyses for this end point

    Secondary: Change in Physical function domain (5-items) score (Impact of Weight on Quality of Life-Lite-Clinical Trials version [IWQOL-Lite-CT])

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    End point title
    		 Change in Physical function domain (5-items) score (Impact of Weight on Quality of Life-Lite-Clinical Trials version [IWQOL-Lite-CT])
    End point description
    The Impact of Weight on Quality of Life Clinical Trials Version (IWQOL-Lite-CT) is designed to assess the impact of changes in weight on patient’s quality of life within the context of clinical trials. IWQOL-Lite-CT is a 20-item questionnaire-based instrument used to assess the impact of body weight changes on subject's overall health-related quality of life (HRQoL). All IWQOL-Lite-CT composite scores range from 0 to 100, with higher scores reflecting better levels of functioning. Results for Physical Function Domain are presented in this presented. The end point was evaluated based on the data from in-trial period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    188
    89
    Units: Score on a scale
        arithmetic mean (standard deviation)
    16.8 ( 20.4 )
    8.3 ( 16.7 )
    No statistical analyses for this end point

    Secondary: Change in body mass index (BMI)

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    End point title
    		 Change in body mass index (BMI)
    End point description
    Change in BMI from baseline (week 0) to end of treatment (week 64) is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    192
    90
    Units: Kilogram per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    -5.3 ( 4.0 )
    -0.9 ( 2.8 )
    No statistical analyses for this end point

    Secondary: Change in waist circumference

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    End point title
    		 Change in waist circumference
    End point description
    Change in waist circumference from baseline (week 0) to end of treatment (week 64) is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    191
    89
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    -12.9 ( 12.3 )
    -3.1 ( 11.2 )
    No statistical analyses for this end point

    Secondary: Change in systolic blood pressure

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    End point title
    		 Change in systolic blood pressure
    End point description
    Change in systolic blood pressure from baseline (week 0) to end of treatment (week 64) is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    192
    90
    Units: Millimeters of mercury (mmHg)
        arithmetic mean (standard deviation)
    -7 ( 15 )
    -5 ( 15 )
    No statistical analyses for this end point

    Secondary: Change in diastolic blood pressure

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    End point title
    		 Change in diastolic blood pressure
    End point description
    Change in diastolic blood pressure from randomisation (week 0) to end of treatment (week 64) is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    192
    90
    Units: mmHg
        arithmetic mean (standard deviation)
    -3 ( 9 )
    -2 ( 10 )
    No statistical analyses for this end point

    Secondary: Change in glycosylated haemoglobin (HbA1c)

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    End point title
    		 Change in glycosylated haemoglobin (HbA1c)
    End point description
    Change in glycosylated haemoglobin (HbA1c) from baseline (week 0) to end of treatment (week 64) is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    190
    86
    Units: Percentage point of HbA1c
        arithmetic mean (standard deviation)
    -0.3 ( 0.3 )
    -0.0 ( 0.2 )
    No statistical analyses for this end point

    Secondary: Change in high density lipoproteins (HDL) cholesterol

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    End point title
    		 Change in high density lipoproteins (HDL) cholesterol
    End point description
    Change in HDL (mmol/L) from baseline (week 0) to end of treatment (week 64) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    182
    85
    Units: Ratio of high density lipoproteins
        geometric mean (geometric coefficient of variation)
    1.04 ( 15.8 )
    0.99 ( 13.7 )
    No statistical analyses for this end point

    Secondary: Change in total cholesterol

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    End point title
    		 Change in total cholesterol
    End point description
    Change in total cholesterol measured in millimoles per liter (mmol/L) from baseline (week 0) to end of treatment (week 64) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    187
    87
    Units: Ratio of total cholesterol
        geometric mean (geometric coefficient of variation)
    0.96 ( 15.3 )
    0.98 ( 16.4 )
    No statistical analyses for this end point

    Secondary: Change in low density lipoprotein (LDL) cholesterol

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    End point title
    		 Change in low density lipoprotein (LDL) cholesterol
    End point description
    Change in LDL (mmol/L) from baseline (week 0) to end of treatment (week 64) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    182
    85
    Units: Ratio of low density lipoproteins
        geometric mean (geometric coefficient of variation)
    0.96 ( 24.0 )
    0.99 ( 25.9 )
    No statistical analyses for this end point

    Secondary: Change in triglycerides

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    End point title
    		 Change in triglycerides
    End point description
    Change in triglycerides (mmol/L) from baseline (week 0) to end of treatment (week 64) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    186
    87
    Units: Ratio of triglycerides
        geometric mean (geometric coefficient of variation)
    0.80 ( 39.2 )
    0.93 ( 36.0 )
    No statistical analyses for this end point

    Secondary: Change in very low density lipoprotein (VLDL)

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    End point title
    		 Change in very low density lipoprotein (VLDL)
    End point description
    Change in VLDL (mmol/L) from baseline (week 0) to end of treatment (week 64) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    186
    87
    Units: Ratio of very low density lipoproteins
        geometric mean (geometric coefficient of variation)
    0.80 ( 38.9 )
    0.92 ( 36.8 )
    No statistical analyses for this end point

    Secondary: Change in free fatty acids

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    End point title
    		 Change in free fatty acids
    End point description
    Change in free fatty acids (mmol/L) from baseline (week 0) to end of treatment (week 64) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    180
    84
    Units: Ratio of free fatty acids
        geometric mean (geometric coefficient of variation)
    0.86 ( 64.2 )
    0.95 ( 76.6 )
    No statistical analyses for this end point

    Secondary: Change in high sensitivity C-Reactive Protein

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    End point title
    		 Change in high sensitivity C-Reactive Protein
    End point description
    Change in high sensitivity C-Reactive Protein (hsCRP) measured in milligram per litre (mg/L) from baseline (week 0) to end of treatment (week 64) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    188
    87
    Units: Ratio of hsCRP
        geometric mean (geometric coefficient of variation)
    0.50 ( 111.9 )
    0.91 ( 122.8 )
    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 measured in mg/dL from baseline (week 0) to end of treatment (week 64) is presented. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    186
    87
    Units: mg/dL
        arithmetic mean (standard deviation)
    -7.3 ( 10.8 )
    0.1 ( 12.0 )
    No statistical analyses for this end point

    Secondary: Change in fasting serum insulin

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    End point title
    		 Change in fasting serum insulin
    End point description
    Change in fasting serum insulin measured in picomoles per liter (pmol/L) from baseline (week 0) to end of treatment (week 64) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period. In-trial observation period: the uninterrupted time interval from the start of randomisation to last trial-related subject-site contact. Full analysis set (FAS) comprised all randomised subjects. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 64)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    180
    84
    Units: Ratio of fasting serum insulin
        geometric mean (geometric coefficient of variation)
    0.74 ( 57.9 )
    1.03 ( 62.5 )
    No statistical analyses for this end point

    Secondary: Number of treatment emergent adverse events

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    End point title
    		 Number of treatment emergent adverse events
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a clinical study participant that is temporally associated with the use of IMP, whether or not considered related to the IMP. All AEs mentioned here are treatment emergent adverse events (TEAE) defined as an event with onset during the on-treatment observation period. On-treatment observation period: from the date of first IMP administration to date of last IMP administration excluding potential off-treatment time intervals of more than 3 consecutive days. Safety analysis set (SAS) included all participants randomly assigned to study treatment and who took at least 1 dose of trial product. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of study (week 71)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    204
    102
    Units: Events
        number (not applicable)
    1239
    432
    No statistical analyses for this end point

    Secondary: Number of treatment emergent serious adverse events

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    End point title
    		 Number of treatment emergent serious adverse events
    End point description
    Number of treatment emergent serious adverse events from baseline (week 0) to end of study (week 71) is presented. A serious adverse event (SAE) is any untoward medical occurrence that fulfils at least one of following criteria: results in death; is life-threatening; requires inpatient or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is congenital anomaly/birth defect; important medical event. The end point was evaluated based on data from on-treatment observation period. On-treatment observation period: from date of first investigational medicinal product (IMP) administration to date of last IMP administration excluding potential off-treatment time intervals of more than 3 consecutive days. Safety analysis set (SAS) included all participants randomly assigned to study treatment and who took at least 1 dose of trial product. Overall number of subjects analyzed = subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of study (week 71)
    End point values
    		 Oral semaglutide 25 mg Placebo
    Number of subjects analysed
    204
    102
    Units: Events
        number (not applicable)
    17
    13
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline (week 0) to end of study (week 71)
    Adverse event reporting additional description
    All presented adverse events (AEs) are treatment emergent adverse events (TEAEs). Treatment emergent adverse events: defined as an event with onset during on-treatment observation period. Safety analysis set (SAS) included all participants randomly assigned to study treatment and who took at least 1 dose of trial product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo tablets matched to oral semaglutide once daily for 64 weeks.

    Reporting group title
    Oral semaglutide 25 mg
    Reporting group description
    		 Subjects received oral semaglutide tablets once daily in a dose escalation manner for 64 weeks: 3 mg (weeks 0 to 4), 7 mg (weeks 5 to 8), 14 mg (weeks 9 to 12), and 25 mg (weeks 13 to 64).

    Serious adverse events
    		 Placebo Oral semaglutide 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 102 (8.82%)
    8 / 204 (3.92%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal neoplasm
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign salivary gland neoplasm
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Sleeve gastrectomy
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian mass
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture displacement
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac aneurysm
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         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 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         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
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (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
    Furuncle
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (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
    Hyponatraemia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 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 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 102 (77.45%)
    172 / 204 (84.31%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 102 (0.98%)
    11 / 204 (5.39%)
         occurrences all number
    1
    14
    Headache
         subjects affected / exposed
    9 / 102 (8.82%)
    24 / 204 (11.76%)
         occurrences all number
    10
    34
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 102 (0.98%)
    15 / 204 (7.35%)
         occurrences all number
    1
    15
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 102 (3.92%)
    15 / 204 (7.35%)
         occurrences all number
    5
    16
    Abdominal pain upper
         subjects affected / exposed
    2 / 102 (1.96%)
    18 / 204 (8.82%)
         occurrences all number
    2
    23
    Dyspepsia
         subjects affected / exposed
    9 / 102 (8.82%)
    37 / 204 (18.14%)
         occurrences all number
    11
    50
    Diarrhoea
         subjects affected / exposed
    9 / 102 (8.82%)
    36 / 204 (17.65%)
         occurrences all number
    10
    61
    Constipation
         subjects affected / exposed
    10 / 102 (9.80%)
    41 / 204 (20.10%)
         occurrences all number
    11
    59
    Eructation
         subjects affected / exposed
    2 / 102 (1.96%)
    21 / 204 (10.29%)
         occurrences all number
    2
    23
    Vomiting
         subjects affected / exposed
    6 / 102 (5.88%)
    63 / 204 (30.88%)
         occurrences all number
    6
    105
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 102 (4.90%)
    16 / 204 (7.84%)
         occurrences all number
    5
    17
    Nausea
         subjects affected / exposed
    19 / 102 (18.63%)
    95 / 204 (46.57%)
         occurrences all number
    27
    157
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 102 (1.96%)
    13 / 204 (6.37%)
         occurrences all number
    2
    14
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 102 (5.88%)
    6 / 204 (2.94%)
         occurrences all number
    6
    6
    Arthralgia
         subjects affected / exposed
    6 / 102 (5.88%)
    6 / 204 (2.94%)
         occurrences all number
    9
    6
    Infections and infestations
    COVID-19
         subjects affected / exposed
    18 / 102 (17.65%)
    41 / 204 (20.10%)
         occurrences all number
    19
    45
    Bronchitis
         subjects affected / exposed
    7 / 102 (6.86%)
    9 / 204 (4.41%)
         occurrences all number
    8
    10
    Urinary tract infection
         subjects affected / exposed
    3 / 102 (2.94%)
    13 / 204 (6.37%)
         occurrences all number
    4
    16
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 102 (8.82%)
    11 / 204 (5.39%)
         occurrences all number
    13
    11
    Tonsillitis
         subjects affected / exposed
    6 / 102 (5.88%)
    5 / 204 (2.45%)
         occurrences all number
    7
    5
    Sinusitis
         subjects affected / exposed
    7 / 102 (6.86%)
    7 / 204 (3.43%)
         occurrences all number
    8
    8
    Nasopharyngitis
         subjects affected / exposed
    27 / 102 (26.47%)
    43 / 204 (21.08%)
         occurrences all number
    40
    59
    Influenza
         subjects affected / exposed
    10 / 102 (9.80%)
    15 / 204 (7.35%)
         occurrences all number
    10
    21
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 102 (0.98%)
    14 / 204 (6.86%)
         occurrences all number
    1
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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