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    Clinical Trial Results:
    Efficacy and safety of semaglutide 2.0 mg s.c. once-weekly compared to semaglutide 1.0 mg s.c. once-weekly in subjects with type 2 diabetes

    Summary
    EudraCT number
    		 2018-004529-96
    Trial protocol
    		 SK   CZ   PL   BG   GR  
    Global end of trial date
    09 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Nov 2021
    First version publication date
    25 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9535-4506
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03989232
    WHO universal trial number (UTN)
    		 U1111-1224-5162
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsværd, Denmark, 2880
    Public contact
    Clinical Transparency and Medical Writing Office (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Transparency and Medical Writing Office (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to establish the superior effect of semaglutide subcutaneous (s.c.) 2.0 milligrams (mg) once-weekly versus semaglutide s.c. 1.0 mg once-weekly on glycaemic control in subjects with type 2 diabetes (T2D), on a background of metformin with or without sulfonyl urea (SU) treatment.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (2016), including archiving of essential documents, and 21 CFR 312.120
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jun 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 96
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Czechia: 15
    Country: Number of subjects enrolled
    Greece: 37
    Country: Number of subjects enrolled
    Hungary: 156
    Country: Number of subjects enrolled
    Japan: 50
    Country: Number of subjects enrolled
    Poland: 136
    Country: Number of subjects enrolled
    Slovakia: 92
    Country: Number of subjects enrolled
    Ukraine: 50
    Country: Number of subjects enrolled
    United States: 309
    Worldwide total number of subjects
    961
    EEA total number of subjects
    532
    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)
    690
    From 65 to 84 years
    270
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 125 sites in Bulgaria (9), Canada (8), Czech Republic (4), Greece (6), Hungary (12), Japan (2), Poland (10), Slovakia (11), Ukraine (5) and the United States (58). 4 sites in the US screened but did not randomize subjects, and 3 sites were approved by the IRB/IEC but did not screen or assign any subjects to treatment.

    Pre-assignment
    Screening details
    		 Subjects with type 2 diabetes (T2D) treated with stable doses of metformin only, or metformin in combination with sulfonylurea (SU), in need of the treatment intensification were randomized 1:1 to once-weekly treatment with semaglutide 2.0 mg or once-weekly treatment with semaglutide 1.0 mg.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The first 12 weeks during escalation all the trial products were packed open-label as all subjects followed the same treatment regimen in this period. From week 13 the subject was to receive trial product which was packed open-label (which contained semaglutide), as well as trial product which was packed blinded (and contained either semaglutide or placebo). The active drug and placebo drug were visually identical.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Semaglutide 1.0 mg
    Arm description
    		 Subjects received subcutaneous (s.c.) injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target dose of 1.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 1.0 mg semaglutide along with s.c. injection of placebo matched to semaglutide 1.0 mg during 12-40 weeks.
    Arm type
    		 Active comparator

    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
    Subjects received s.c. injection of placebo matched to semaglutide 1.0 mg during 12-40 weeks.

    Investigational medicinal product name
    Semaglutide B 1.34 mg/ml PDS290
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received s.c. injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target maintenance dose was reached.

    Arm title
    		 Semaglutide 2.0 mg
    Arm description
    		 Subjects received s.c. injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target maintenance dose of 2.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 2.0 mg during 12-40 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide B 1.34 mg/ml PDS290
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received s.c. injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target maintenance dose was reached.

    Number of subjects in period 1
    		Semaglutide 1.0 mg Semaglutide 2.0 mg
    Started
    481
    480
    Completed
    471
    462
    Not completed
    10
    18
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    6
    6
         Lost to follow-up
    3
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 1.0 mg
    Reporting group description
    		 Subjects received subcutaneous (s.c.) injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target dose of 1.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 1.0 mg semaglutide along with s.c. injection of placebo matched to semaglutide 1.0 mg during 12-40 weeks.

    Reporting group title
    Semaglutide 2.0 mg
    Reporting group description
    		 Subjects received s.c. injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target maintenance dose of 2.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 2.0 mg during 12-40 weeks.

    Reporting group values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg Total
    Number of subjects
    		 481 480 961
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.2 ± 9.9 57.9 ± 10.0 -
    Gender Categorical
    Units: Subjects
        Female
    		 197 201 398
        Male
    		 284 279 563

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 1.0 mg
    Reporting group description
    		 Subjects received subcutaneous (s.c.) injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target dose of 1.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 1.0 mg semaglutide along with s.c. injection of placebo matched to semaglutide 1.0 mg during 12-40 weeks.

    Reporting group title
    Semaglutide 2.0 mg
    Reporting group description
    		 Subjects received s.c. injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target maintenance dose of 2.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 2.0 mg during 12-40 weeks.

    Primary: Change in HbA1c (%-points)

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    End point title
    		 Change in HbA1c (%-points)
    End point description
    Change from baseline (week 0) to week 40 in glycosylated haemoglobin (HbA1c) was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first; and 'In-trial' observation period which started at the date of randomisation and ended at the first of the following dates, both inclusive: follow-up visit (week 47), death, subject withdrew informed consent, last contact for subject lost to follow-up. The FAS included all randomized subjects. In below table, n=number of subjects contributed to the analysis.
    End point type
    Primary
    End point timeframe
    From baseline (week 0) to week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    481
    480
    Units: Percentage change of HbA1c
    arithmetic mean (standard deviation)
        On-treatment without rescue medication (n=422,423)
    -2.0 ± 1.0
    -2.2 ± 1.0
        In-trial (n=466,456)
    -1.9 ± 1.0
    -2.2 ± 1.1
    Statistical analysis title
    		 Semaglutide 2.0 mg - Semaglutide 1.0 mg
    Statistical analysis description
    Imputation of missing data was handled by multiple imputation (MI) assuming that missing data were missed at random (MAR). The imputation was performed separately within each treatment group defined by randomised treatment.
    Comparison groups
    Semaglutide 2.0 mg v Semaglutide 1.0 mg
    Number of subjects included in analysis
    961
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 -0.11
    Statistical analysis title
    		 In-trial: Semaglutide 2.0 mg - Semaglutide 1.0 mg
    Statistical analysis description
    Imputation of missing data was handled by MI assuming that missing data were missed at random. The imputation was performed by imputing missing week 40 data separately within groups defined by randomised treatment and treatment status at week 40.
    Comparison groups
    Semaglutide 1.0 mg v Semaglutide 2.0 mg
    Number of subjects included in analysis
    961
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0098
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 -0.04

    Secondary: Change in body weight (kg)

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    End point title
    		 Change in body weight (kg)
    End point description
    Change from baseline (week 0) to week 40 in body weight was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first; and 'In-trial' observation period which started at the date of randomisation and ended at the first of the following dates, both inclusive: follow-up visit (week 47), death, subject withdrew informed consent, last contact for subject lost to follow-up. The FAS included all randomized subjects. In the below table, n=number of subjects contributed to the analysis
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    481
    480
    Units: Kilogram (kg)
    arithmetic mean (standard deviation)
        On-treatment without rescue medication (n=425,434)
    -6.0 ± 5.8
    -7.0 ± 5.8
        In-trial (n=467,457)
    -5.7 ± 5.9
    -6.7 ± 5.9
    No statistical analyses for this end point

    Secondary: Change in fasting plasma glucose (FPG) (mmol/l)

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    End point title
    		 Change in fasting plasma glucose (FPG) (mmol/l)
    End point description
    Change from baseline (week 0) to week 40 in FPG was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first. The FAS included all randomized subjects. Number of subjects analyzed=number of subjects contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    423
    429
    Units: Millimoles per liter (mmol/L)
        arithmetic mean (standard deviation)
    -3.2 ± 2.8
    -3.4 ± 3.1
    No statistical analyses for this end point

    Secondary: Change in body mass index (BMI) (kg/m2)

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    End point title
    		 Change in body mass index (BMI) (kg/m2)
    End point description
    Change from baseline (week 0) to week 40 in BMI was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first. The FAS included all randomized participants. Number of subjects analyzed=number of subjects contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    425
    434
    Units: Kilogram per squaremeter (Kg/m^2)
        arithmetic mean (standard deviation)
    -2.1 ± 2.1
    -2.5 ± 2.1
    No statistical analyses for this end point

    Secondary: Change in waist circumference (cm)

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    End point title
    		 Change in waist circumference (cm)
    End point description
    Change from baseline (week 0) to week 40 in waist circumference was evaluated. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first. The FAS included all randomized subjects. Number of subjects analyzed=number of participants contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    423
    433
    Units: Centimeter (cm)
        arithmetic mean (standard deviation)
    -5.2 ± 6.1
    -5.9 ± 6.2
    No statistical analyses for this end point

    Secondary: HbA1c less than 7% at week 40 (yes/no)

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    End point title
    		 HbA1c less than 7% at week 40 (yes/no)
    End point description
    Percentage of subjects who achieved HbA1c < 7.0% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first. Missing HbA1c assessment at week 40 was imputed using observed data from subjects within same treatment group. The FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    At week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    481
    480
    Units: Percentahe of subjects
        number (not applicable)
    57.5
    67.6
    No statistical analyses for this end point

    Secondary: Weight loss 5% or more at week 40

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    End point title
    		 Weight loss 5% or more at week 40
    End point description
    Percentage of subjects who achieved weight loss ≥5% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first. Missing body weight assessment at week 40 was imputed using observed data from subjects within same treatment group. The FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    At week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    481
    480
    Units: Percentage of subjects
        number (not applicable)
    51.3
    59.2
    No statistical analyses for this end point

    Secondary: HbA1c 6.5% or less at week 40 (yes/no)

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    End point title
    		 HbA1c 6.5% or less at week 40 (yes/no)
    End point description
    Percentage of subjects who achieved HbA1c ≤ 6.5% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first. Missing HbA1c assessment at week 40 was imputed using observed data from subjects within same treatment group. The FAS included all randomized participants.
    End point type
    Secondary
    End point timeframe
    At week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    481
    480
    Units: Percentage of subjects
        number (not applicable)
    38.5
    51.7
    No statistical analyses for this end point

    Secondary: Weight loss 10% or more at week 40 (yes/no)

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    End point title
    		 Weight loss 10% or more at week 40 (yes/no)
    End point description
    Percentage of subjects who achieved weight loss ≥10% is presented. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose of trial product to either first initiation of rescue medication or the day of last dose of trial product plus 14 days, whichever came first. Missing body weight assessment at week 40 was imputed using observed data from subjects within same treatment group. The FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    At week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    481
    480
    Units: Percentage of subjects
        number (not applicable)
    22.6
    28.4
    No statistical analyses for this end point

    Secondary: Number of treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemic episodes

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    End point title
    		 Number of treatment emergent severe or blood glucose confirmed symptomatic hypoglycaemic episodes
    End point description
    Hypoglycaemic episodes defined as treatment-emergent if the onset of the episode occurs within the on-treatment observation period. Severe or blood glucose (BG)-confirmed symptomatic hypoglycaemia is an episode that required assistance from another person for recovery and blood glucose-confirmed by a plasma glucose value <3.1 mmol/L (56 milligrams per deciliter (mg/dL)) with symptoms consistent with hypoglycaemia. Results are based on the 'on-treatment' observation period, which started at the date of first dose of trial product and ended at the first date of any of the following: the follow-up visit (week 47), the treatment discontinuation follow-up visit (end of treatment + 7 weeks), the date of last dose of trial product +49 days or the end-date for the ‘in-trial’ observation period. The SAS included all subjects exposed to at least one dose of trial product.
    End point type
    Secondary
    End point timeframe
    From first dose to week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    480
    479
    Units: Number of episodes
    28
    21
    No statistical analyses for this end point

    Secondary: Change in pulse rate (bpm)

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    End point title
    		 Change in pulse rate (bpm)
    End point description
    Change from baseline (week 0) to week 40 in pulse is presented. Results are based on the 'on-treatment' observation period, which started at the date of first dose of trial product and ended at the first date of any of the following: the follow-up visit (week 47), the treatment discontinuation follow-up visit (end of treatment + 7 weeks), the date of last dose of trial product +49 days or the end-date for the ‘in-trial’ observation period. The SAS included all subjects exposed to at least one dose of trial product. Number of subjects analyzed=number of subjects contributed to the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to week 40
    End point values
    		 Semaglutide 1.0 mg Semaglutide 2.0 mg
    Number of subjects analysed
    444
    442
    Units: Beats per minute (bpm)
        arithmetic mean (standard deviation)
    2.8 ± 10.0
    3.3 ± 9.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Weeks 0-47
    Adverse event reporting additional description
    All presented AEs are TEAEs. A TEAE was defined as an event that had onset during the on-treatment period. Results are based on the SAS which comprised of all participants exposed to at least one dose of trial product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Semaglutide 2.0 mg
    Reporting group description
    		 Subjects received s.c. injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target maintenance dose of 2.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 2.0 mg during 12-40 weeks.

    Reporting group title
    Semaglutide 1.0 mg
    Reporting group description
    		 Subjects received subcutaneous (s.c.) injection of semaglutide once-weekly for 40 weeks in a fixed-dose escalation regimen, with dose doubling every 4 weeks until the target dose of 1.0 mg was reached: 0.25 mg during 0-4 weeks followed by 0.5 mg during 4-8 weeks followed by 1.0 mg during 8-12 weeks and then 1.0 mg semaglutide along with s.c. injection of placebo matched to semaglutide 1.0 mg during 12-40 weeks.

    Serious adverse events
    		 Semaglutide 2.0 mg Semaglutide 1.0 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 479 (4.38%)
    25 / 480 (5.21%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dilatation
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (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 discomfort
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Smear cervix abnormal
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 479 (0.21%)
    2 / 480 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 479 (0.21%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 479 (0.00%)
    3 / 480 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuromyelitis optica spectrum disorder
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 479 (0.42%)
    2 / 480 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis membranous
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Asymptomatic bacteriuria
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 479 (0.21%)
    0 / 480 (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
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 479 (0.00%)
    2 / 480 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 479 (0.00%)
    2 / 480 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 479 (0.00%)
    1 / 480 (0.21%)
         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
    		 Semaglutide 2.0 mg Semaglutide 1.0 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    132 / 479 (27.56%)
    126 / 480 (26.25%)
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    37 / 479 (7.72%)
    32 / 480 (6.67%)
         occurrences all number
    55
    40
    Nausea
         subjects affected / exposed
    69 / 479 (14.41%)
    70 / 480 (14.58%)
         occurrences all number
    98
    98
    Diarrhoea
         subjects affected / exposed
    45 / 479 (9.39%)
    42 / 480 (8.75%)
         occurrences all number
    51
    83
    Dyspepsia
         subjects affected / exposed
    16 / 479 (3.34%)
    25 / 480 (5.21%)
         occurrences all number
    17
    26
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 479 (6.05%)
    18 / 480 (3.75%)
         occurrences all number
    29
    18

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Aug 2019
    - Updated text in Section 7.7 of the protocol, to clarify requirements for stable background medication during the trial. - Updated text in Section 9.4.3 of the protocol, to clarify that the end of treatment eye examination can be performed within 3 weeks prior to the visit; but that the results should be available at the end of treatment visit.
    13 Mar 2020
    Introduction of partial database lock.
    03 Jul 2020
    Revision of primary analysis for the treatment policy estimand; updated imputation method for missing data.

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

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

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