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    Clinical Trial Results:
    Efficacy and safety of subcutaneous semaglutide 2.4 mg once-weekly in subjects with obesity and prediabetes (STEP 10)

    Summary
    EudraCT number
    		 2020-002939-29
    Trial protocol
    		 FI   DK   ES  
    Global end of trial date
    14 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2024
    First version publication date
    26 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9536-4734
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05040971
    WHO universal trial number (UTN)
    		 U1111-1253-1956
    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
    01 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the superiority of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo, both as adjuncts to a reduced-calorie diet and increased physical activity in subjects with obesity and prediabetes, on body weight and reversal to normoglycemia.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Oct 2013) and International Council for Harmonisation (ICH) Good Clinical Practice, including archiving of essential documents (May 1996) and European Standard (EN) International Organization for Standardization (ISO) 14155 Part 1 and 2 and Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 312.120.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Sep 2021
    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: 75
    Country: Number of subjects enrolled
    Denmark: 23
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    Finland: 32
    Country: Number of subjects enrolled
    United Kingdom: 45
    Worldwide total number of subjects
    207
    EEA total number of subjects
    87
    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)
    176
    From 65 to 84 years
    30
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 30 sites in 5 countries as follows: Canada (15 sites), Denmark (2 sites), Finland (2 sites), Spain (3 sites) and United Kingdom (8 sites).

    Pre-assignment
    Screening details
    		 Trial has Main phase (52-week treatment period: 16 weeks dose escalation, 36 weeks maintenance dose) & Extension phase (28-week off-treatment for body weight, glycaemic & cardiovascular assessment). Subjects were randomized 2:1 to receive semaglutide 2.4mg or placebo as an adjunct to a reduced-calorie diet and increased physical activity.

    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
    		 Semaglutide 2.4 mg
    Arm description
    		 Subjects received once-weekly subcutaneous (s.c) injection of 0.25 milligram (mg) Semaglutide administered using a DV3396 pen-injector followed by a fixed-dose escalation regimen, with dose increase every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week) until the maintenance dose of 2.4 mg after 16 weeks. Treatment was continued on the maintenance dose of 2.4 mg Semaglutide once weekly for an additional 36 weeks until week 52. The treatment was an adjunct to a reduced-calorie diet and increased physical activity.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Once-weekly subcutaneous injection of semaglutide was administered for 16 weeks with escalating doses for every 4 weeks (0.25 mg, 0.5 mg, 1.0 mg, and 1.7 mg) followed by a maintenance period of 52 weeks with a dose of 2.4 mg.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received once-weekly subcutaneous (s.c) injection of 0.25 milligram (mg) placebo matched to 2.4 mg Semaglutide administered using a DV3396 pen-injector followed by a fixed-dose escalation regimen, with dose increase every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week) until the maintenance dose of 2.4 mg after 16 weeks. Treatment was continued on the maintenance dose of 2.4 mg placebo matched to 2.4 mg Semaglutide once weekly for an additional 36 weeks until week 52. The treatment was an adjunct to a reduced-calorie diet and increased physical activity.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Once-weekly subcutaneous injection of semaglutide placebo was administered for 16 weeks with escalating doses for every 4 weeks (0.25 mg, 0.5 mg, 1.0 mg, and 1.7 mg) followed by a maintenance period of 52 weeks with a dose of 2.4 mg.

    Number of subjects in period 1
    		Semaglutide 2.4 mg Placebo
    Started
    138
    69
    Full analysis set (FAS)
    138
    69
    Safety analysis set (SAS)
    138
    69
    Completed
    128
    64
    Not completed
    10
    5
         Adverse event, serious fatal
    2
    -
         Consent withdrawn by subject
    -
    2
         Lost to follow-up
    8
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects received once-weekly subcutaneous (s.c) injection of 0.25 milligram (mg) Semaglutide administered using a DV3396 pen-injector followed by a fixed-dose escalation regimen, with dose increase every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week) until the maintenance dose of 2.4 mg after 16 weeks. Treatment was continued on the maintenance dose of 2.4 mg Semaglutide once weekly for an additional 36 weeks until week 52. The treatment was an adjunct to a reduced-calorie diet and increased physical activity.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received once-weekly subcutaneous (s.c) injection of 0.25 milligram (mg) placebo matched to 2.4 mg Semaglutide administered using a DV3396 pen-injector followed by a fixed-dose escalation regimen, with dose increase every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week) until the maintenance dose of 2.4 mg after 16 weeks. Treatment was continued on the maintenance dose of 2.4 mg placebo matched to 2.4 mg Semaglutide once weekly for an additional 36 weeks until week 52. The treatment was an adjunct to a reduced-calorie diet and increased physical activity.

    Reporting group values
    		 Semaglutide 2.4 mg Placebo Total
    Number of subjects
    		 138 69 207
    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)
    		 120 56 176
        From 65-84 years
    		 17 13 30
        85 years and over
    		 1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53 ( 11 ) 53 ( 11 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 100 47 147
        Male
    		 38 22 60

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects received once-weekly subcutaneous (s.c) injection of 0.25 milligram (mg) Semaglutide administered using a DV3396 pen-injector followed by a fixed-dose escalation regimen, with dose increase every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week) until the maintenance dose of 2.4 mg after 16 weeks. Treatment was continued on the maintenance dose of 2.4 mg Semaglutide once weekly for an additional 36 weeks until week 52. The treatment was an adjunct to a reduced-calorie diet and increased physical activity.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received once-weekly subcutaneous (s.c) injection of 0.25 milligram (mg) placebo matched to 2.4 mg Semaglutide administered using a DV3396 pen-injector followed by a fixed-dose escalation regimen, with dose increase every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week) until the maintenance dose of 2.4 mg after 16 weeks. Treatment was continued on the maintenance dose of 2.4 mg placebo matched to 2.4 mg Semaglutide once weekly for an additional 36 weeks until week 52. The treatment was an adjunct to a reduced-calorie diet and increased physical activity.

    Primary: Change in body weight

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    End point title
    		 Change in body weight
    End point description
    Change in body weight from randomisation (week 0) to end of treatment (week 52) is presented. The endpoint was evaluated based on the data from both in-trial and on-treatment observation periods. In-trial observation period was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. On-treatment: The time period where subjects were treated with study product. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data. n= number of subjects evaluated per each arm respectively for this outcome measure.
    End point type
    Primary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    129
    66
    Units: Percentage (%) of body weight
    arithmetic mean (standard deviation)
        In-trial (n= 129, 66)
    -14.4 ( 7.9 )
    -2.7 ( 4.3 )
        On-treatment (n= 117, 60)
    -15.4 ( 7.2 )
    -2.6 ( 4.4 )
    Statistical analysis title
    		 Statistical Analysis 2
    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
    Semaglutide 2.4 mg v Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    -13.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.2
         upper limit
    		 -11.4
    Notes
    [1] - Hypothetical estimand: Total number of subjects included in statistical analysis is 166. The number given here is auto-calculated by the system.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 52 responses were analysed using an analysis of covariance model (ANCOVA) with randomised treatment as factor and baseline body weight as covariate.
    Comparison groups
    Semaglutide 2.4 mg v Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -11.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.97
         upper limit
    		 -9.42
    Notes
    [2] - Treatment policy estimand

    Primary: Change to normoglycemia (Normoglycemia is defined as having both HbA1c below 6.0% (below 42 mmol/mol) and FPG below 5.5 mmol/L (below 99 mg/dL)

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    End point title
    		 Change to normoglycemia (Normoglycemia is defined as having both HbA1c below 6.0% (below 42 mmol/mol) and FPG below 5.5 mmol/L (below 99 mg/dL)
    End point description
    Number of subjects in glycaemic categories, "normoglycaemia, pre-diabetes and type 2 diabetes" at Week 52 are presented. These categories were set as per the following criteria: 1) Normoglycaemia: glycosylated haemoglobin (HbA1c) lesser than (<) 6.0 percentage (%) and fasting plasma glucose (FPG) lesser than (<) 5.5 millimoles per liter (mmol/L). 2) Pre-diabetes: 6.0% lesser than or equal (≤) HbA1c lesser than (<) 6.5% or 5.5 mmol/L lesser than or equal (≤) FPG lesser than (<) 7.0 mmol/L or non-verified type 2 diabetes. 3) Type 2 diabetes: HbA1c greater than or equal (≥) 6.5% or FPG greater than or equal (≥) 7.0 mmol/L. Type 2 diabetes needs to verified with a retest within 4 weeks. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data. n= number of subjects evaluated per each arm respectively for this outcome measure.
    End point type
    Primary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    127
    64
    Units: Subjects
        In-trial: Normoglycemia (n= 127, 64)
    103
    9
        In-trial: Pre-diabetes (n= 127, 64)
    23
    53
        In-trial: Type 2 diabetes (n= 127, 64)
    1
    2
        On-treatment: Normoglycemia (n= 115, 60)
    97
    8
        On-treatment: Pre-diabetes (n= 115, 60)
    18
    51
        On-treatment: Type 2 diabetes (n= 115, 60)
    0
    1
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 52 responses were analysed using a logistic regression model with randomised treatment as factor and baseline glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) as covariates.
    Comparison groups
    Semaglutide 2.4 mg v Placebo
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    19.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.68
         upper limit
    		 45.21
    Notes
    [3] - Treatment policy estimand: Total number of subjects included in statistical analysis is 190. The number given here is auto-calculated by the system.
    Statistical analysis title
    		 Statistical Analysis 2
    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 glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) as covariates.
    Comparison groups
    Semaglutide 2.4 mg v Placebo
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    43.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.03
         upper limit
    		 104.8
    Notes
    [4] - Hypothetical estimand: Total number of subjects included in statistical analysis is 165. The number given here is auto-calculated by the system.

    Secondary: Change in HbA1c

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    End point title
    		 Change in HbA1c
    End point description
    Change in glycosylated haemoglobin (HbA1c) from randomisation (week 0) to end of treatment (week 52) is presented. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    129
    63
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -0.4 ( 0.3 )
    0.1 ( 0.2 )
    No statistical analyses for this end point

    Secondary: Change in FPG

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    End point title
    		 Change in FPG
    End point description
    Change in fasting plasma glucose (FPG) from randomisation (week 0) to end of treatment (week 52) is presented. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    127
    63
    Units: millimoles per liter (mmol/L)
        arithmetic mean (standard deviation)
    -0.8 ( 0.6 )
    -0.3 ( 0.7 )
    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 randomisation (week 0) to end of treatment (week 52) is presented. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    129
    66
    Units: centimeter (cm)
        arithmetic mean (standard deviation)
    -11.6 ( 8.7 )
    -2.8 ( 5.4 )
    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 randomisation (week 0) to end of treatment (week 52) is presented. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    129
    66
    Units: millimeters of mercury (mmHg)
        arithmetic mean (standard deviation)
    -9 ( 13 )
    -1 ( 13 )
    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 (measured in mmol/L) from randomisation (week 0) to end of treatment (week 52) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    126
    62
    Units: Ratio of triglycerides
        geometric mean (geometric coefficient of variation)
    0.80 ( 36.4 )
    0.96 ( 30.6 )
    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 mmol/L) from randomisation (week 0) to end of treatment (week 52) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    127
    63
    Units: Ratio of total cholesterol
        geometric mean (geometric coefficient of variation)
    0.94 ( 16.1 )
    1.01 ( 15.7 )
    No statistical analyses for this end point

    Secondary: Change in High density lipoprotein (HDL) cholesterol

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    End point title
    		 Change in High density lipoprotein (HDL) cholesterol
    End point description
    Change in high density lipoprotein (HDL) cholesterol (measured in mmol/L) from randomisation (week 0) to end of treatment (week 52) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    119
    61
    Units: Ratio of HDL cholesterol
        geometric mean (geometric coefficient of variation)
    1.02 ( 12.4 )
    0.99 ( 11.7 )
    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 low density lipoprotein (LDL) cholesterol (measured in mmol/L) from randomisation (week 0) to end of treatment (week 52) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    118
    61
    Units: Ratio of LDL cholesterol
        geometric mean (geometric coefficient of variation)
    0.93 ( 26.6 )
    1.03 ( 23.6 )
    No statistical analyses for this end point

    Secondary: Change in very low density lipoprotein (VLDL) cholesterol

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    End point title
    		 Change in very low density lipoprotein (VLDL) cholesterol
    End point description
    Change in very low density lipoprotein (VLDL) cholesterol (measured in mmol/L) from randomisation (week 0) to end of treatment (week 52) is presented as ratio to baseline. The endpoint was evaluated based on the data from in-trial observation period which was defined as the time period where the subject was assessed in the study. The in-trial observation period for a subject begins on the date of randomisation and ends at the first of the following dates (both inclusive): End of trial visit, withdrawal of consent, last contact with subjects (for subjects lost to follow-up), death. FAS included all randomised subjects. 'Number of subjects analysed' = subjects with available data.
    End point type
    Secondary
    End point timeframe
    From randomisation (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    125
    62
    Units: Ratio of VLDL cholesterol
        geometric mean (geometric coefficient of variation)
    0.80 ( 36.5 )
    0.96 ( 30.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation (week 0) to week 57
    Adverse event reporting additional description
    All the presented adverse events are treatment emergent adverse events (TEAEs). TEAEs: events that had onset date during on-treatment period, time period in which subjects was considered exposed to trial product. SAS during on-treatment included all subjects randomly assigned to treatment who took at least one dose of study product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received once-weekly subcutaneous (s.c) injection of 0.25 milligram (mg) placebo matched to 2.4 mg Semaglutide administered using a DV3396 pen-injector followed by a fixed-dose escalation regimen, with dose increase every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week) until the maintenance dose of 2.4 mg after 16 weeks. Treatment was continued on the maintenance dose of 2.4 mg placebo matched to 2.4 mg Semaglutide once weekly for an additional 36 weeks until week 52. The treatment was an adjunct to a reduced-calorie diet and increased physical activity.

    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects received once-weekly subcutaneous (s.c) injection of 0.25 milligram (mg) Semaglutide administered using a DV3396 pen-injector followed by a fixed-dose escalation regimen, with dose increase every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week) until the maintenance dose of 2.4 mg after 16 weeks. Treatment was continued on the maintenance dose of 2.4 mg Semaglutide once weekly for an additional 36 weeks until week 52. The treatment was an adjunct to a reduced-calorie diet and increased physical activity.

    Serious adverse events
    		 Placebo Semaglutide 2.4 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 69 (8.70%)
    12 / 138 (8.70%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anaplastic thyroid cancer
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Bladder neoplasm
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         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
    1 / 69 (1.45%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 138 (1.45%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Embedded device
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 138 (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
    Endophthalmitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Submandibular abscess
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 138 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal disease
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 138 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Semaglutide 2.4 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 69 (43.48%)
    93 / 138 (67.39%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 69 (7.25%)
    6 / 138 (4.35%)
         occurrences all number
    6
    8
    Dizziness
         subjects affected / exposed
    1 / 69 (1.45%)
    7 / 138 (5.07%)
         occurrences all number
    1
    7
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 69 (5.80%)
    7 / 138 (5.07%)
         occurrences all number
    4
    8
    Constipation
         subjects affected / exposed
    0 / 69 (0.00%)
    25 / 138 (18.12%)
         occurrences all number
    0
    29
    Diarrhoea
         subjects affected / exposed
    7 / 69 (10.14%)
    17 / 138 (12.32%)
         occurrences all number
    7
    31
    Vomiting
         subjects affected / exposed
    1 / 69 (1.45%)
    16 / 138 (11.59%)
         occurrences all number
    1
    27
    Dyspepsia
         subjects affected / exposed
    3 / 69 (4.35%)
    12 / 138 (8.70%)
         occurrences all number
    4
    21
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 69 (0.00%)
    7 / 138 (5.07%)
         occurrences all number
    0
    8
    Nausea
         subjects affected / exposed
    3 / 69 (4.35%)
    40 / 138 (28.99%)
         occurrences all number
    3
    50
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 69 (2.90%)
    7 / 138 (5.07%)
         occurrences all number
    2
    7
    COVID-19
         subjects affected / exposed
    21 / 69 (30.43%)
    48 / 138 (34.78%)
         occurrences all number
    21
    55
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 69 (1.45%)
    11 / 138 (7.97%)
         occurrences all number
    1
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2021
    Reporting of serious adverse events (SAEs) in the extension phase. Update of time frame for evaluation of treatment intensity of antihypertensive and lipid-lowering medication. Inclusion of assumption on unequal variances in the primary analysis of change in body weight.

    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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