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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

    Summary
    EudraCT number
    		 2019-004452-11
    Trial protocol
    		 CZ   HU   NL   DE   DK  
    Global end of trial date
    18 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 May 2024
    First version publication date
    04 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EX9536-4665
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04788511
    WHO universal trial number (UTN)
    		 U1111-1243-4358
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, 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
    10 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effects of semaglutide subcutaneous 2.4 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).
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Oct 2013) and ICH Good Clinical Practice, including archiving of essential documents (May 1996) and EN ISO 14155 Part 1 and 2 and FDA 21 CFR 312.120.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Mar 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: 30
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Czechia: 38
    Country: Number of subjects enrolled
    Germany: 47
    Country: Number of subjects enrolled
    Denmark: 24
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    United Kingdom: 47
    Country: Number of subjects enrolled
    Hungary: 60
    Country: Number of subjects enrolled
    Israel: 39
    Country: Number of subjects enrolled
    Netherlands: 28
    Country: Number of subjects enrolled
    Poland: 62
    Country: Number of subjects enrolled
    United States: 86
    Worldwide total number of subjects
    529
    EEA total number of subjects
    291
    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)
    175
    From 65 to 84 years
    344
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 83 sites in 13 countries, as follows: Argentina (6), Australia (5), Hungary (8), Czech Republic (5), Poland (6), Spain (3), Netherlands (6), Denmark (3), United States (16), Canada (4), Israel (5), Germany (7) and United Kingdom (9).

    Pre-assignment
    Screening details
    		 A total of 817 subjects were screened for this trial, out of which 281 subjects were screening failures and seven subjects were withdrawn before randomisation. Overall, 529 eligible subjects were randomised (1:1) to treatment with semaglutide (263) and placebo (266).

    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 with obesity (body mass index [BMI] greater than or equal to (≥) 30.0 kilogram per square meter (kg/m^2) related heart failure with preserved ejection fraction received semaglutide 2.4 milligrams (mg) once weekly by subcutaneous injection (in the abdomen, thigh or upper arm). Subjects initially received 0.25 mg of semaglutide. The dose was then escalated every fourth week with increments of 0.25 mg for 16 weeks until the target dose of 2.4 mg was reached. The treatment period was 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects with obesity (BMI ≥30.0 kg/m^2) related heart failure with preserved ejection fraction received semaglutide 2.4 mg once weekly by subcutaneous injection (in the abdomen, thigh or upper arm).

    Arm title
    		 Placebo
    Arm description
    		 Subjects with obesity (BMI ≥30.0 kg/m^2) related heart failure with preserved ejection fraction received placebo once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) for 52 weeks. The dose escalation and maintenance of placebo matched that of semaglutide.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matched to semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects with obesity (BMI ≥30.0) kg/m^2) related heart failure with preserved ejection fraction 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
    263
    266
    Full Analysis Set (FAS)
    263
    266
    Safety Analysis Set (SAS)
    263
    266
    Completed
    256
    254
    Not completed
    7
    12
         Adverse event, serious fatal
    3
    4
         Consent withdrawn by subject
    2
    1
         Lost to follow-up
    2
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects with obesity (body mass index [BMI] greater than or equal to (≥) 30.0 kilogram per square meter (kg/m^2) related heart failure with preserved ejection fraction received semaglutide 2.4 milligrams (mg) once weekly by subcutaneous injection (in the abdomen, thigh or upper arm). Subjects initially received 0.25 mg of semaglutide. The dose was then escalated every fourth week with increments of 0.25 mg for 16 weeks until the target dose of 2.4 mg was reached. The treatment period was 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with obesity (BMI ≥30.0 kg/m^2) related heart failure with preserved ejection fraction received placebo once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) for 52 weeks. The dose escalation and maintenance of placebo matched that of semaglutide.

    Reporting group values
    		 Semaglutide 2.4 mg Placebo Total
    Number of subjects
    		 263 266 529
    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 (18-65 years)
    		 84 91 175
        From 65-75 years
    		 113 104 217
        75-85 years
    		 60 67 127
        85 years and over
    		 6 4 10
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69 ± 9 68 ± 10 -
    Sex: Female, Male
    Units: subjects
        Female
    		 149 148 297
        Male
    		 114 118 232
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 8 13 21
        White
    		 255 252 507
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 15 21 36
        Not Hispanic or Latino
    		 248 245 493
        Unknown or Not Reported
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69 ± 9 68 ± 10 -

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects with obesity (body mass index [BMI] greater than or equal to (≥) 30.0 kilogram per square meter (kg/m^2) related heart failure with preserved ejection fraction received semaglutide 2.4 milligrams (mg) once weekly by subcutaneous injection (in the abdomen, thigh or upper arm). Subjects initially received 0.25 mg of semaglutide. The dose was then escalated every fourth week with increments of 0.25 mg for 16 weeks until the target dose of 2.4 mg was reached. The treatment period was 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with obesity (BMI ≥30.0 kg/m^2) related heart failure with preserved ejection fraction received placebo once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) for 52 weeks. The dose escalation and maintenance of placebo matched that of semaglutide.

    Primary: Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score

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    End point title
    		 Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score
    End point description
    The KCCQ is standardised 23-item, self-administered instrument that quantifies heart failure symptoms (frequency, severity, and recent change), physical limitation, quality of life, and social limitation. The overall summary score (OSS) and all domains have been independently demonstrated to be valid, reliable, and responsive to clinical change. KCCQ-CSS includes symptom and physical limitation domains of the KCCQ. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. The endpoint was evaluated based on data from in-trial period. In-trial period was defined as uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all randomised subjects for this trial. Here, "Number of Subjects Analysed (N)" signifies those subjects who had an observed value 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
    243
    237
    Units: Score on a scale
        arithmetic mean (standard deviation)
    16.8 ± 17.9
    10.3 ± 17.3
    Statistical analysis title
    		 Semaglutide 2.4 mg vs Placebo
    Statistical analysis description
    The responses at week 52 were analysed using an analysis of covariance model with randomised treatment and stratification (BMI<35.0 kg/m^2, BMI>=35.0 kg/m^2) as factors and baseline KCCQ-CSS as covariate.
    Comparison groups
    Semaglutide 2.4 mg v Placebo
    Number of subjects included in analysis
    480
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Estimated Treatment Difference
    Point estimate
    7.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.8
         upper limit
    		 10.9
    Notes
    [1] - The analysis was based on the in-trial period using the FAS population. Missing observations at week 52 were multiple (x1000) imputed from retrieved subjects of the same randomised treatment arm.

    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 endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    246
    242
    Units: Percentage of body weight
        arithmetic mean (standard deviation)
    -13.9 ± 8.1
    -2.5 ± 5.6
    Statistical analysis title
    		 Semaglutide 2.4 mg vs Placebo
    Statistical analysis description
    The responses at week 52 were analysed using an analysis of covariance model with randomised treatment and stratification (BMI<35.0 kg/m^2, BMI>=35.0 kg/m^2) as factors and baseline body weight (kg) as covariate.
    Comparison groups
    Semaglutide 2.4 mg v Placebo
    Number of subjects included in analysis
    488
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Estimated Treatment Difference
    Point estimate
    -10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.9
         upper limit
    		 -9.4
    Notes
    [2] - The analysis was based on the in-trial period using the FAS population. Missing observations at week 52 were multiple (x1000) imputed from retrieved subjects of the same randomised treatment arm.

    Secondary: Change in Six-minute Walking Distance (6MWD)

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    End point title
    		 Change in Six-minute Walking Distance (6MWD)
    End point description
    Observed mean change from baseline (week 0) in 6 minutes walking distance (6MWD) test to end of treatment (week 52) is presented. The 6MWD is a common test of functional exercise capacity that assesses the distance a subject can walk in 6 minutes. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    240
    225
    Units: Meters
        arithmetic mean (standard deviation)
    23.5 ± 59.2
    5.8 ± 62.7
    No statistical analyses for this end point

    Secondary: Change in C-Reactive Protein (CRP): Ratio to baseline

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    End point title
    		 Change in C-Reactive Protein (CRP): Ratio to baseline
    End point description
    Change in high sensitivity C-reactive protein measured in ratio of C-reactive protein to baseline (week -2) at end of treatment (week 52) is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    241
    243
    Units: Ratio of C-reactive protein
        geometric mean (geometric coefficient of variation)
    0.55 ± 121.5
    0.92 ± 105.3
    No statistical analyses for this end point

    Secondary: The Hierarchical Composite Endpoint: Percentage of Wins of Subjects Pairs

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    End point title
    		 The Hierarchical Composite Endpoint: Percentage of Wins of Subjects Pairs
    End point description
    Hierarchical composite endpoint from baseline (week 0) to end of study (week 57) consists of the components: time to all-cause death, number of heart failure events requiring hospitalisation or urgent heart failure visit, time to first heart failure event requiring hospitalisation or urgent heart failure visit, difference at least 15 in KCCQ CSS change from baseline to 52 weeks, difference at least 10 in KCCQ CSS change from baseline to 52 weeks, difference at least 5 in KCCQ CSS change from baseline to 52 weeks and difference at least 30 meters in 6MWD change from baseline to 52 weeks. It was analysed by the win-ratio approach using all subjects pairs across treatment groups. Overall summary of wins in each treatment group will be presented. The endpoint was evaluated based on data from in-trial period. In-trial period was defined as uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all randomised subjects for this trial.
    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
    263
    266
    Units: Percentage of wins of subjects pairs
        number (not applicable)
    60.1
    34.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving 10 Percent (%) Weight Loss (Yes/No)

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    End point title
    		 Percentage of Subjects Achieving 10 Percent (%) Weight Loss (Yes/No)
    End point description
    Percentage of subjects who achieved 10% weight loss (yes/no) from baseline (week 0) to end of treatment (week 52) is presented. In the reported data, 'Yes' infers percentage of subjects who have achieved 10% weight loss whereas 'No' infers percentage of subjects who have not achieved 10% weight loss. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    246
    242
    Units: Percentage of subjects
    number (not applicable)
        No
    34.1
    90.5
        Yes
    65.9
    9.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving 15% Weight Loss (Yes/No)

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    End point title
    		 Percentage of Subjects Achieving 15% Weight Loss (Yes/No)
    End point description
    Percentage of subjects who achieved 15% weight loss (yes/no) from baseline (week 0) to end of treatment (week 52) is presented. In the reported data, 'Yes' infers percentage of subjects who have achieved 15% weight loss whereas 'No' infers percentage of subjects who have not achieved 15% weight loss. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    246
    242
    Units: Percentage of subjects
    number (not applicable)
        No
    56.1
    97.9
        Yes
    43.9
    2.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Improving 5 Points or more in KCCQ Clinical Summary Score (Yes/No)

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    End point title
    		 Percentage of Subjects Improving 5 Points or more in KCCQ Clinical Summary Score (Yes/No)
    End point description
    Percentage of subjects improving 5 points or more in KCCQ-CSS from baseline to end of treatment is presented. The KCCQ is standardised 23-item, self-administered instrument that quantifies heart failure symptoms(frequency, severity, and recent change), physical limitation, quality of life, and social limitation. KCCQ-CSS includes symptom and physical limitation domains of KCCQ. Scores are transformed to range of 0-100, in which higher scores reflect better health status. The reported data, 'Yes' infers percentage of subjects who have improved 5 points or more in score whereas 'No' infers percentage of subjects who have not improved 5 points or more in score. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomization to date of last contact with trial site. FAS included all randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    243
    237
    Units: Percentage of subjects
    number (not applicable)
        No
    24.7
    36.3
        Yes
    75.3
    63.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving 20% Weight Loss (Yes/No)

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    End point title
    		 Percentage of Subjects Achieving 20% Weight Loss (Yes/No)
    End point description
    Percentage of subjects who achieved 20% weight loss (yes/no) from baseline (week 0) to end of treatment (week 52) is presented. In the reported data, 'Yes' infers percentage of subjects who have achieved 20% weight loss whereas 'No' infers percentage of subjects who have not achieved 20% weight loss The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    246
    242
    Units: Percentage of Subjects
    number (not applicable)
        No
    76.4
    99.6
        Yes
    23.6
    0.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Improving 10 Points or more in KCCQ Clinical Summary Score (Yes/No)

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    End point title
    		 Percentage of Subjects Improving 10 Points or more in KCCQ Clinical Summary Score (Yes/No)
    End point description
    Percentage of subjects improving 10 points or more in KCCQ-CSS from baseline to end of treatment is presented. The KCCQ is standardised 23-item, self-administered instrument that quantifies heart failure symptoms(frequency, severity, and recent change), physical limitation, quality of life, and social limitation. KCCQ-CSS includes the symptom and physical limitation domains of the KCCQ. Scores are transformed to range of 0-100, in which higher scores reflect better health status. In reported data, 'Yes' infers percentage of subjects who have improved 5 points or more in score whereas 'No' infers percentage of subjects who have not improved 10 points or more in score. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as uninterrupted time interval from date of randomization to date of last contact with trial site. FAS included all randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    243
    237
    Units: Percentage of subjects
    number (not applicable)
        No
    36.6
    51.5
        Yes
    63.4
    48.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Threshold for Clinically Meaningful within-subjects Change in KCCQ-CSS (PGI-S)

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    End point title
    		 Percentage of Subjects Achieving Threshold for Clinically Meaningful within-subjects Change in KCCQ-CSS (PGI-S)
    End point description
    The patient global impression of status (PGI-S) for KCCQ was used to rate subjects’ symptoms of heart failure using a 4-category ordinal scale (no symptoms, mild, moderate, severe). 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, and social limitation. OSS and all domains have been independently demonstrated to be valid, reliable, and responsive to clinical change. KCCQ-CSS includes the symptom and physical limitation domains of the KCCQ. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. The threshold was defined as the mean change in KCCQ-CSS in those subjects with an one-category improvement in PGI-S from baseline to week 52. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    243
    237
    Units: Percentage of subjects
        number (not applicable)
    43.2
    32.5
    No statistical analyses for this end point

    Secondary: Change in KCCQ Overall Summary Score (KCCQ-OSS)

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    End point title
    		 Change in KCCQ Overall Summary Score (KCCQ-OSS)
    End point description
    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, and social limitation. The overall summary score and all domains have been independently demonstrated to be valid, reliable, and responsive to clinical change. KCCQ-CSS includes the symptom and physical limitation domains of the KCCQ while KCCQ-OSS includes the symptom, physical limitation, quality of life, and social limitation domains. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    243
    237
    Units: Score on a scale
        arithmetic mean (standard deviation)
    16.8 ± 18.3
    10.9 ± 17.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Threshold for Clinically Meaningful within-subjects Change in 6MWD (PGI-S)

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    End point title
    		 Percentage of Subjects Achieving Threshold for Clinically Meaningful within-subjects Change in 6MWD (PGI-S)
    End point description
    Observed mean change from baseline in 6 minutes walking distance (6MWD) test using PGI-S is evaluated for this endpoint. The 6MWD is a common test of functional exercise capacity that assesses the distance a subject can walk in 6 minutes. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. The threshold was defined as the mean change in 6MWD in those subjects with an one-category improvement in PGI-S from baseline to week 52. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    240
    225
    Units: Percentage of subjects
        number (not applicable)
    42.5
    28.0
    No statistical analyses for this end point

    Secondary: Change in Systolic blood pressure (SBP)

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    End point title
    		 Change in Systolic blood pressure (SBP)
    End point description
    Observed mean change in systolic blood pressure from baseline (week -2) to end of treatment (week 52) is presented. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value 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
    246
    243
    Units: millimetre of mercury (mmHg)
        arithmetic mean (standard deviation)
    -6.4 ± 19.0
    -1.1 ± 17.5
    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 from baseline (week 0) to week 52 in waist circumference is evaluated. Waist circumference is defined as the abdominal circumference located midway between the lower rib margin and the iliac crest. Measurement must be obtained in standing position with a non-stretchable measuring tape and to the nearest cm or inch. The tape should touch the skin but not compress soft tissue and twists in the tape should be avoided. The subject should be asked to breathe normally. The same measuring tape should be used throughout the trial. The endpoint was evaluated based on the data from in-trial period. In-trial period was defined as the uninterrupted time interval from date of randomisation to date of last contact with trial site. FAS included all the randomised subjects for this trial. Here, "N" signifies those subjects who had an observed value at week 52.
    End point type
    Secondary
    End point timeframe
    From baseline (week 0) to end of treatment (visit 52)
    End point values
    		 Semaglutide 2.4 mg Placebo
    Number of subjects analysed
    246
    240
    Units: Centimeter
        arithmetic mean (standard deviation)
    -12.0 ± 8.5
    -2.8 ± 7.4
    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
    All presented adverse events (AEs) are treatment-emergent AEs. It was defined as event that had onset during on-treatment period (date of first trial product administration to date of last trial product administration excluding potential off-treatment time intervals triggered by at least 5 consecutive missed doses).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Semaglutide 2.4 mg
    Reporting group description
    		 Subjects with obesity (BMI ≥30.0 kg/m^2) related heart failure with preserved ejection fraction received semaglutide 2.4 mg once weekly by subcutaneous injection (in the abdomen, thigh or upper arm). Subjects initially received 0.25 mg of semaglutide. The dose was then escalated every fourth week with increments of 0.25 mg for 16 weeks until the target dose of 2.4 mg was reached. The treatment period was 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with obesity (BMI ≥30.0 kg/m^2) related heart failure with preserved ejection fraction received placebo once weekly by subcutaneous injection (in the abdomen, thigh or upper arm) for 52 weeks. The dose escalation and maintenance of placebo matched that of semaglutide.

    Serious adverse events
    		 Semaglutide 2.4 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 263 (13.31%)
    71 / 266 (26.69%)
         number of deaths (all causes)
    3
    4
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Haematoma evacuation
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         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
    Acute respiratory failure
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiration abnormal
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         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
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical observation
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial injury
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         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 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         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
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 263 (1.14%)
    9 / 266 (3.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 263 (0.00%)
    12 / 266 (4.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 263 (0.00%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal discomfort
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 263 (1.14%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (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 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 263 (0.76%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         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
    5 / 263 (1.90%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint stiffness
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 263 (0.38%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 263 (0.76%)
    0 / 266 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 263 (0.00%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    1 / 263 (0.38%)
    3 / 266 (1.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 263 (0.38%)
    2 / 266 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 263 (0.76%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 263 (0.38%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 263 (0.00%)
    1 / 266 (0.38%)
         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 2.4 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 263 (35.36%)
    57 / 266 (21.43%)
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    17 / 263 (6.46%)
    7 / 266 (2.63%)
         occurrences all number
    18
    8
    Vomiting
         subjects affected / exposed
    17 / 263 (6.46%)
    3 / 266 (1.13%)
         occurrences all number
    22
    3
    Nausea
         subjects affected / exposed
    45 / 263 (17.11%)
    7 / 266 (2.63%)
         occurrences all number
    51
    8
    Diarrhoea
         subjects affected / exposed
    24 / 263 (9.13%)
    10 / 266 (3.76%)
         occurrences all number
    28
    16
    Infections and infestations
    COVID-19
         subjects affected / exposed
    36 / 263 (13.69%)
    41 / 266 (15.41%)
         occurrences all number
    36
    43

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Mar 2021
    The overall rationale for the changes implemented in the amended protocol was to account for collection of vital status and to include additional blood sampling for pharmacokinetic assessment following comments received from the Food and Drug administration (FDA). Plasma semaglutide concentrations were to be used to describe the exposure-response analysis. In addition, information regarding the COVID-19 pandemic was included.
    18 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 subject-reported endpoint combined with objective measures and events. To account for this, a hierarchical composite endpoint was added to confirmatory 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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