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    Clinical Trial Results:
    Effect of Semaglutide 2.4 mg once weekly on function and symptoms in subjects with obesity-related heart failure with preserved ejection fraction, and type 2 diabetes

    Summary
    EudraCT number
    		 2020-004170-22
    Trial protocol
    		 NL   DE   HU   SE   PL   AT   IT   ES   CZ  
    Global end of trial date
    11 Oct 2023

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

    Trial information

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    Trial identification
    Sponsor protocol code
    EX9536-4773
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04916470
    WHO universal trial number (UTN)
    		 U1111-1257-5069
    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
    02 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to investigate the effects of semaglutide subcutaneous (s.c.) 2.4 milligrams (mg) once-weekly on physical function, symptoms and body weight compared with placebo, both added to standard of care, in subjects with obesity-related heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki last amended by the 64th World Medical Association General Assembly, October 2013 and International Council for Harmonisation (ICH) Good Clinical Practice, including archiving of essential documents, and 21 U.S. Code of Federal Regulations (CFR) 312.120, 312.50 and 312.56.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    15 Jun 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
    Argentina: 57
    Country: Number of subjects enrolled
    Austria: 19
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Czechia: 34
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Spain: 39
    Country: Number of subjects enrolled
    United Kingdom: 28
    Country: Number of subjects enrolled
    Hungary: 71
    Country: Number of subjects enrolled
    India: 55
    Country: Number of subjects enrolled
    Israel: 35
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    Poland: 82
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United States: 69
    Worldwide total number of subjects
    616
    EEA total number of subjects
    331
    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)
    193
    From 65 to 84 years
    409
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 108 sites in 16 countries. Number of sites that randomised subjects are as follows: Argentina (6), Austria (4), Canada (6), Czech Republic (4) Germany (7), Hungary (10), India (9), Israel (5), Italy (6), Japan (6), Netherlands (5), Poland (6), Spain (3), Sweden (2), United Kingdom (7) and United States (22).

    Pre-assignment
    Screening details
    		 The trial included a 16-week dose escalation period with a dose increase every 4th week, a maintenance period and a 5-week follow-up period.

    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 semaglutide 2.4 milligrams (mg) once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) as an add-on to standard of care. Subjects initially received 0.25 mg of semaglutide. The dose was then escalated every fourth week for a period of 16 weeks until the target dose of 2.4 mg was reached as an add-on to standard of care. The treatment period was 52 weeks. Subjects were followed up for 5 weeks after end of treatment till week 57.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide D
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received semaglutide 2.4 mg once weekly by subcutaneous injection (in the abdomen, thigh or upper arm).

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) for 52 weeks as an add-on to standard of care. The dose escalation and maintenance of placebo matched that of semaglutide. Subjects were followed up for 5 weeks after end of treatment till week 57.
    Arm type
    		 Experimental

    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 placebo matched to semaglutide once weekly by subcutaneous injection (in the abdomen, thigh or upper arm).

    Number of subjects in period 1
    		Semaglutide 2.4 mg Placebo
    Started
    310
    306
    Exposed
    310
    306
    Full analysis set (FAS)
    310
    306
    Safety analysis set (SAS)
    310
    306
    Completed
    292
    291
    Not completed
    18
    15
         Consent withdrawn by subject
    5
    3
         Death
    6
    10
         Lost to follow-up
    7
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects received semaglutide 2.4 milligrams (mg) once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) as an add-on to standard of care. Subjects initially received 0.25 mg of semaglutide. The dose was then escalated every fourth week for a period of 16 weeks until the target dose of 2.4 mg was reached as an add-on to standard of care. The treatment period was 52 weeks. Subjects were followed up for 5 weeks after end of treatment till week 57.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) for 52 weeks as an add-on to standard of care. The dose escalation and maintenance of placebo matched that of semaglutide. Subjects were followed up for 5 weeks after end of treatment till week 57.

    Reporting group values
    		 Semaglutide 2.4 mg Placebo Total
    Number of subjects
    		 310 306 616
    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)
    		 98 95 193
        From 65-84 years
    		 206 203 409
        85 years and over
    		 6 8 14
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68 ( 9 ) 69 ( 9 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 128 145 273
        Male
    		 182 161 343
    Race
    Units: Subjects
        Asian
    		 45 31 76
        Black or African American
    		 13 5 18
        Other
    		 1 2 3
        White
    		 251 268 519
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 38 38 76
        Not Hispanic or Latino
    		 272 268 540
    Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS)
    The KCCQ is a standardised 23-item, self-administered instrument that quantifies heart failure symptoms (frequency, severity, and recent change), physical limitation, quality of life (QOL), and social limitation. Scores are transformed to a range of 0 to 100 in which higher scores reflect better health status. KCCQ-CSS includes the symptom and physical limitation domains of the KCCQ. Full analysis set included all randomised subjects.
    Units: Score on a scale
        arithmetic mean (standard deviation)
    		 58.8 ( 20.3 ) 56.4 ( 19.7 ) -
    High Sensitive C-Reactive Protein
    Full analysis set included all randomised subjects
    Units: Milligrams per liter (mg/L)
        arithmetic mean (standard deviation)
    		 6.7 ( 9.0 ) 7.2 ( 14.1 ) -
    Six minute walking test
    The six minute walk test is a direct and timed measure of walk distance. The goal is for the participant to walk as far as possible in six minutes without running. Full analysis set included all randomised subjects
    Units: Meters (m)
        arithmetic mean (standard deviation)
    		 279.7 ( 96.6 ) 276.7 ( 93.5 ) -
    Body weight
    Full analysis set included all randomised subjects.
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    		 106.4 ( 20.9 ) 105.2 ( 21.4 ) -

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects received semaglutide 2.4 milligrams (mg) once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) as an add-on to standard of care. Subjects initially received 0.25 mg of semaglutide. The dose was then escalated every fourth week for a period of 16 weeks until the target dose of 2.4 mg was reached as an add-on to standard of care. The treatment period was 52 weeks. Subjects were followed up for 5 weeks after end of treatment till week 57.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) for 52 weeks as an add-on to standard of care. The dose escalation and maintenance of placebo matched that of semaglutide. Subjects were followed up for 5 weeks after end of treatment till week 57.

    Primary: Change in KCCQ (Kansas City Cardiomyopathy Questionnaire)-CSS (clinical summary score)

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    End point title
    		 Change in KCCQ (Kansas City Cardiomyopathy Questionnaire)-CSS (clinical summary score)
    End point description
    Change in KCCQ-CSS from baseline (week 0) to end of treatment (week 52) is presented. The KCCQ is a standardised 23-item, self-administered instrument that quantifies heart failure symptoms (frequency, severity, and recent change), physical limitation, quality of life (QOL), and social limitation. Scores were transformed to a range of 0 to 100 in which higher scores reflected better health status. KCCQ-Clinical Summary Score (CSS) included the symptom and physical limitation domains of the KCCQ. The outcome data was evaluated based on the in-trial observation period and the full analysis set (FAS). The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). Full analysis set included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Primary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    281
    272
    Units: Score on a scale
        arithmetic mean (standard deviation)
    14.4 ( 18.3 )
    7.6 ( 18.8 )
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Missing observations at week 52 were multiple (x1000) imputed using available measurements at week 52 from subjects of the same randomized treatment arm (using a missing at random (MAR) assumption). Missing observations due to cardiovascular (CV) death or previous heart failure (HF) event were single imputed using change from baseline to the overall lowest KCCQ-CSS value across treatment arms and time points. Results were combined using Rubin's rule.
    Comparison groups
    Semaglutide 2.4 mg v Placebo
    Number of subjects included in analysis
    553
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.1
         upper limit
    		 10.4
    Notes
    [1] - The responses at week 52 were analysed using an an analysis of covariance (ANCOVA) with randomised treatment & stratification (body mass index [BMI] less than 35.0 kilogram per meter square [kg/m^2], BMI more than equal to 35.0 kg/m^2) as factors and baseline KCCQ-CSS as covariate for each of the 1000 complete data sets. Results were combined using Rubin's rule.

    Primary: Change in body weight

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    End point title
    		 Change in body weight
    End point description
    Change in body weight from baseline (week 0) to end of treatment (week 52) is presented. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Primary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    286
    278
    Units: Percentage (%) change in body weight
        arithmetic mean (standard deviation)
    -10.2 ( 6.8 )
    -3.2 ( 5.9 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Missing observations at week 52 were multiple (x1000) imputed using available measurements at week 52 from subjects of the same randomized treatment arm (using a missing at random (MAR) assumption). Results were combined using Rubin's rule.
    Comparison groups
    Semaglutide 2.4 mg v Placebo
    Number of subjects included in analysis
    564
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.6
         upper limit
    		 -5.2
    Notes
    [2] - The responses at week 52 were analysed using an an analysis of covariance (ANCOVA) with randomised treatment & stratification (body mass index [BMI] less than 35.0 kilogram per meter square [kg/m^2], BMI more than equal to 35.0 kg/m^2) as factors and baseline KCCQ-CSS as covariate for each of the 1000 complete data sets. Results were combined using Rubin's rule.

    Secondary: Hierarchical composite endpoint

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    End point title
    		 Hierarchical composite endpoint
    End point description
    The hierarchical composite endpoint is presented. Analysis (win-ratio) of the hierarchical composite endpoint was based on direct comparisons of each participant randomised to semaglutide 2.4 mg and placebo within each stratum. A ‘treatment winner’ (1000 imputations) based on similar observation time was declared based on endpoint hierarchy. Outcome data was evaluated based on in-trial observation period which was defined as time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death) and FAS. Missing observations at week 52 for KCCQ-CSS and body weight were multiple (x1000) imputed (by MAR assumption) using available measurements at week 52 from participants of same randomized treatment arm. Missing KCCG-CSS observations due to CV death or previous HF event were single imputed to overall lowest KCCQ-CSS value across treatment arms and time points. FAS included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of study (week 57)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    310
    306
    Units: Number of wins
    number (not applicable)
        Time to all-cause death
    2796
    1814
        Number of heart failure events
    4434
    1171
        Time to first heart failure event
    34
    26
        Change in KCCQ-CSS >= 15 point difference
    30618
    17303
        Change in KCCQ-CSS >=10 point difference
    6250
    4763
        Change in KCCQ-CSS >=5 point difference
    6925
    5912
        Change in 6MWD >=30 metre difference
    4607
    3920
    No statistical analyses for this end point

    Secondary: Change in six-minute walking distance

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    End point title
    		 Change in six-minute walking distance
    End point description
    Change in six-minute walking distance (6MWD) from baseline (week 0) to end of treatment (week 52) is presented. The 6 Minute Walk Test is a direct and timed measure of walk distance. The goal is for the subject to walk as far as possible in six minutes without running. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    281
    265
    Units: Metres
        arithmetic mean (standard deviation)
    16.9 ( 54.3 )
    3.8 ( 49.8 )
    No statistical analyses for this end point

    Secondary: Change in C-Reactive Protein

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    End point title
    		 Change in C-Reactive Protein
    End point description
    Change in C-Reactive Protein from baseline (week -2) to end of treatment (week 52) is presented. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week -2) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    286
    277
    Units: Ratio to baseline of C-Reactive Protein
        geometric mean (geometric coefficient of variation)
    0.58 ( 146.6 )
    0.91 ( 128.4 )
    No statistical analyses for this end point

    Secondary: Subjects achieving 10% weight loss or more (Yes/No)

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    End point title
    		 Subjects achieving 10% weight loss or more (Yes/No)
    End point description
    Subjects achieving 10% weight loss or more (Yes/No) from baseline (week 0) to end of treatment (week 52) is presented. In the reported data, 'Yes' infers number of subjects who have achieved 10% weight loss or more whereas 'No' infers number of subjects who have not achieved 10% weight loss or more. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    286
    278
    Units: Subjects
        Yes
    147
    29
        No
    139
    249
    No statistical analyses for this end point

    Secondary: Subjects achieving 15% weight loss or more (Yes/No)

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    End point title
    		 Subjects achieving 15% weight loss or more (Yes/No)
    End point description
    Subjects achieving 15% weight loss or more (Yes/No) from baseline (week 0) to end of treatment (week 52) is presented. In the reported data, 'Yes' infers number of subjects who have achieved 15% weight loss or more whereas 'No' infers number of subjects who have not achieved 15% weight loss or more. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    286
    278
    Units: Subjects
        Yes
    64
    11
        No
    222
    267
    No statistical analyses for this end point

    Secondary: Subjects achieving 20% weight loss or more (Yes/No)

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    End point title
    		 Subjects achieving 20% weight loss or more (Yes/No)
    End point description
    Subjects achieving 20% weight loss or more (Yes/No) from baseline (week 0) to end of treatment (week 52) is presented. In the reported data, 'Yes' infers number of subjects who have achieved 20% weight loss or more whereas 'No' infers number of subjects who have not achieved 20% weight loss or more. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    286
    278
    Units: Subjects
        Yes
    21
    5
        No
    265
    273
    No statistical analyses for this end point

    Secondary: Subjects improving 5 points or more in KCCQ clinical summary score (Yes/No)

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    End point title
    		 Subjects improving 5 points or more in KCCQ clinical summary score (Yes/No)
    End point description
    Subjects improving 5 points or more in KCCQ clinical summary score (Yes/No) from baseline (week 0) to end of treatment (week 52) is presented. The KCCQ is a standardised 23-item, self-administered instrument that quantifies heart failure symptoms (frequency, severity, and recent change), physical limitation, quality of life (QOL), and social limitation. Scores are transformed to a range of 0 to 100 in which higher scores reflect better health status. KCCQ-clinical summary score (CSS) includes the symptom and physical limitation domains of the KCCQ. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    281
    272
    Units: Subjects
        Yes
    205
    149
        No
    76
    123
    No statistical analyses for this end point

    Secondary: Subjects achieving threshold for clinically meaningful within-subject change in six minute walking distance (6MWD)

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    End point title
    		 Subjects achieving threshold for clinically meaningful within-subject change in six minute walking distance (6MWD)
    End point description
    Subjects achieving threshold for clinically meaningful within-subject change in 6MWD (PGI-S) from baseline (week 0) to end of treatment (week 52) is presented. The six minute walk test (6MWT) is a direct and timed measure of walk distance. The goal is for the subject to walk as far as possible in six minutes without running. The PGI-S for six minute walk test (6MWT) was used to rate any difficulty that participants were experiencing in walking quickly using a 5-category ordinal scale (not at all difficult, a little difficult, moderately difficult, very difficult, or unable to walk quickly). The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    281
    265
    Units: Subjects
    148
    104
    No statistical analyses for this end point

    Secondary: Change in KCCQ overall summary score (OSS)

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    End point title
    		 Change in KCCQ overall summary score (OSS)
    End point description
    Change in KCCQ-OSS from baseline (week 0) to end of treatment (week 52) is presented. The KCCQ is a standardised 23-item, self-administered instrument that quantifies heart failure symptoms (frequency, severity, and recent change), physical limitation, QOL, and social limitation. Scores are transformed to a range of 0 to 100 in which higher scores reflect better health status. KCCQ-OSS included the symptom, physical limitation, quality of life, and social limitation domains. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    281
    272
    Units: Score on a scale
        arithmetic mean (standard deviation)
    14.4 ( 18.1 )
    7.6 ( 18.6 )
    No statistical analyses for this end point

    Secondary: Subjects improving 10 points or more in KCCQ clinical summary score (Yes/No)

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    End point title
    		 Subjects improving 10 points or more in KCCQ clinical summary score (Yes/No)
    End point description
    Subjects improving 10 points or more in KCCQ clinical summary score (Yes/No) from baseline (week 0) to end of treatment (week 52) is presented. The KCCQ is a standardised 23-item, self-administered instrument that quantifies heart failure symptoms (frequency, severity, and recent change), physical limitation, QOL, and social limitation. Scores are transformed to a range of 0 to 100 in which higher scores reflect better health status. KCCQ-CSS includes the symptom and physical limitation domains of the KCCQ. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    281
    272
    Units: Subjects
        Yes
    163
    116
        No
    118
    156
    No statistical analyses for this end point

    Secondary: Subjects achieving threshold for clinically meaningful within-subject change in KCCQ-CSS

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    End point title
    		 Subjects achieving threshold for clinically meaningful within-subject change in KCCQ-CSS
    End point description
    Subjects achieving threshold for clinically meaningful within-subject change in KCCQ-CSS (PGI-S) from week 0 to week 52 is presented. KCCQ is standardised 23-item instrument that quantifies heart failure symptoms (frequency, severity, and recent change), physical limitation, QOL, and social limitation. Scores are transformed to range of 0 to 100 in which higher scores reflect better health status. KCCQ-CSS includes the symptom and physical limitation domains of KCCQ. PGI-S for KCCQ was used to rate participants’ symptoms of heart failure in last two weeks using a 4-category ordinal scale (no symptoms, mild, moderate, severe). Outcome data was evaluated based on in-trial observation period which was defined as time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death) and FAS. FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    281
    272
    Units: Subjects
    120
    83
    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 52) is presented. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    284
    277
    Units: Centimetre (cm)
        arithmetic mean (standard deviation)
    -8.9 ( 7.9 )
    -2.4 ( 7.2 )
    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 -2) to end of treatment (week 52) is presented. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week -2) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    286
    278
    Units: Millimetres of mercury (mmHg)
        arithmetic mean (standard deviation)
    -4.0 ( 16.9 )
    -2.9 ( 16.8 )
    No statistical analyses for this end point

    Secondary: Change in glycated haemoglobin (HbA1c)

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    End point title
    		 Change in glycated haemoglobin (HbA1c)
    End point description
    Change in HbA1c from baseline (week 0) to end of treatment (week 52) in percentage-point is presented. The outcome data was evaluated based on the in-trial observation period and FAS. The in-trial period was defined as the time interval from date of randomisation to date of last contact with trial site (or date of withdrawal of informed consent or death). FAS included all randomised subjects. Number of subjects analysed = Subjects with available data for this endpoint at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (week 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    284
    270
    Units: Percentage-point of HbA1c
        arithmetic mean (standard deviation)
    -0.8 ( 1.1 )
    0.1 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Number of treatment emergent severe or clinically significant hypoglycaemia episodes

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    End point title
    		 Number of treatment emergent severe or clinically significant hypoglycaemia episodes
    End point description
    Number of treatment emergent severe or clinically significant hypoglycaemia episodes from baseline (week 0) to end of trial (week 57) is presented. Clinically significant hypoglycemic episode is defined as blood glucose concentration of less than 54 milligrams per deciliter (mg/dL) which is sufficiently low to indicate serious, clinically important hypoglycaemia. Severe hypoglycemic episode is defined as hypoglycaemia associated with severe cognitive impairment requiring external assistance for recovery. The outcome data was evaluated based on on-treatment period. A time-point was considered as ‘on-treatment’ if any dose of trial product had been administered within the prior 5 weeks (35 days). Safety analysis set (SAS) included all subjects randomly assigned to trial treatment and who took at least one dose of trial product.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of study (week 57)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    310
    306
    Units: Episodes
        number (not applicable)
    20
    30
    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 trial (week 57)
    Adverse event reporting additional description
    Results were based on safety analysis set, subjects randomly assigned to trial treatment & took at least 1 dose of trial product. Presented AE were treatment emergent, that initiated/worsened while being on treatment. AE were reported from on-treatment period & in-trial period (deaths, cardiovascular disorders, neoplasms, retinal disorders).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) for 52 weeks as an add-on to standard of care. The dose escalation and maintenance of placebo matched that of semaglutide. Subjects were followed up for 5 weeks after end of treatment till week 57.

    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects received semaglutide 2.4 milligrams (mg) once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) as an add-on to standard of care. Subjects initially received 0.25 mg of semaglutide. The dose was then escalated every fourth week for a period of 16 weeks until the target dose of 2.4 mg was reached as an add-on to standard of care. The treatment period was 52 weeks. Subjects were followed up for 5 weeks after end of treatment till week 57.

    Serious adverse events
    		 Placebo Semaglutide 2.4 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    88 / 306 (28.76%)
    55 / 310 (17.74%)
         number of deaths (all causes)
    10
    6
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign neoplasm of adrenal gland
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ductal adenocarcinoma of pancreas
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung carcinoma cell type unspecified stage IV
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic arteriosclerosis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 306 (0.33%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Gastric bypass
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 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 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (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 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Allergy to vaccine
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (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
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 306 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 306 (0.65%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septum perforation
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (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
    Acetabulum fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 306 (0.00%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural hypotension
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic arthritis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    5 / 306 (1.63%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 306 (0.33%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         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
    6 / 306 (1.96%)
    5 / 310 (1.61%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmic storm
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia supraventricular
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    22 / 306 (7.19%)
    4 / 310 (1.29%)
         occurrences causally related to treatment / all
    2 / 30
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    3 / 306 (0.98%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 306 (0.98%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 306 (0.33%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetic cardiomyopathy
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 306 (0.65%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Coma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 306 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normocytic anaemia
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic cyst
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         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
    Blister
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 306 (1.31%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 306 (0.98%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (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
    Bursal haematoma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Facet joint syndrome
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nose deformity
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oligoarthritis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 306 (0.98%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (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
    Bacterial sepsis
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 306 (0.98%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 306 (0.00%)
    2 / 310 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Keratitis fungal
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 306 (2.94%)
    3 / 310 (0.97%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 306 (0.65%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 306 (0.65%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 310 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 310 (0.32%)
         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
    60 / 306 (19.61%)
    104 / 310 (33.55%)
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    30 / 306 (9.80%)
    13 / 310 (4.19%)
         occurrences all number
    40
    17
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    18 / 306 (5.88%)
    55 / 310 (17.74%)
         occurrences all number
    22
    77
    Vomiting
         subjects affected / exposed
    7 / 306 (2.29%)
    26 / 310 (8.39%)
         occurrences all number
    8
    32
    Diarrhoea
         subjects affected / exposed
    20 / 306 (6.54%)
    42 / 310 (13.55%)
         occurrences all number
    23
    61
    Infections and infestations
    COVID-19
         subjects affected / exposed
    31 / 306 (10.13%)
    26 / 310 (8.39%)
         occurrences all number
    32
    26
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 306 (3.27%)
    16 / 310 (5.16%)
         occurrences all number
    11
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2021
    The overall rationale for the changes implemented in the amended protocol was to account for collection of vital status for subjects lost to follow-up to align internally with other Novo Nordisk trials, following health authority feedback.
    23 Sep 2022
    The overall rationale for the changes implemented in the amended protocol was to anticipate an increasing interest in reporting results in a manner that reflects the clinical relevance across different domains including patient-reported outcomes combined with objective measures and events. To account for this, a hierarchical composite endpoint was added to confirmatory secondary endpoints, and additional endpoints related to weight loss, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and 6-minute walk distance (6MWD) were added to supportive secondary endpoints.

    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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