ClinicalTrials.gov
ClinicalTrials.gov Menu

Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN™ 6)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01720446
Recruitment Status : Completed
First Posted : November 2, 2012
Results First Posted : March 15, 2018
Last Update Posted : July 18, 2018
Sponsor:
Information provided by (Responsible Party):
Novo Nordisk A/S

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Diabetes
Diabetes Mellitus, Type 2
Interventions Drug: semaglutide
Drug: placebo
Enrollment 3297

Recruitment Details The trial was conducted at 229 sites in 20 countries. Country (sites): Algeria (4), Argentina (7), Australia (8), Brazil (8), Bulgaria (5), Canada (13), Denmark (5), Germany (7), Israel (6), Italy (6), Malaysia (6), Mexico (9), Poland (5), Russia (11), Spain (6), Taiwan (4), Thailand (5), Turkey (10), United Kingdom (8) and United States (96).
Pre-assignment Details Subjects could be anti-glycaemic drug naïve, or treated with 1 or 2 oral anti diabetic drugs (OADs), or treated with human NPH insulin or long-acting insulin analogue or pre-mixed insulin, alone or in combination with 1 or 2 OAD(s).
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Period Title: Overall Study
Started 826 822 824 825
Premature Treatment Discontinuers 164 [1] 186 [1] 151 [1] 159 [1]
Completed 812 [2] 811 [2] 804 [2] 805 [2]
Not Completed 14 11 20 20
Reason Not Completed
Lost to Follow-up             12             6             16             16
Withdrawal by Subject             2             5             4             4
[1]
Premature treatment discontinuers were allowed to continue participation in the trial.
[2]
Subjects who did not permanently discontinue treatment prematurely.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg Total
Hide Arm/Group Description Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks. Total of all reporting groups
Overall Number of Baseline Participants 826 822 824 825 3297
Hide Baseline Analysis Population Description
Analysis was performed on full analysis set which included all randomised subjects.
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
50-64 years 440 415 419 425 1699
65-74 years 312 324 324 317 1277
75-84 years 71 76 75 79 301
85 and over 3 7 6 4 20
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
Female
331
  40.1%
304
  37.0%
342
  41.5%
318
  38.5%
1295
  39.3%
Male
495
  59.9%
518
  63.0%
482
  58.5%
507
  61.5%
2002
  60.7%
Glycosylated haemoglobin  
Mean (Standard Deviation)
Unit of measure:  Percentage of glycosylated haemoglobin
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
8.67  (1.39) 8.73  (1.51) 8.70  (1.49) 8.70  (1.45) 8.70  (1.46)
Fasting plasma glucose  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
185.4  (66.09) 182.9  (68.04) 185.8  (68.23) 184.6  (63.08) 184.7  (66.37)
Body weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
91.80  (20.25) 92.86  (21.05) 91.83  (20.35) 91.90  (20.75) 92.09  (20.60)
LDL-cholesterol  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
89.62  (39.08) 89.72  (34.49) 89.01  (38.35) 91.14  (37.90) 89.87  (37.49)
HDL-cholesterol  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
45.92  (13.00) 44.97  (12.42) 45.82  (12.92) 44.61  (12.26) 45.33  (12.66)
Systolic BP  
Mean (Standard Deviation)
Unit of measure:  mmHg
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
136.1  (17.97) 135.8  (16.96) 135.8  (16.16) 134.8  (17.45) 135.6  (17.15)
Diastolic BP  
Mean (Standard Deviation)
Unit of measure:  mmHg
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
77.10  (9.78) 76.88  (10.21) 77.54  (9.85) 76.66  (10.21) 77.05  (10.02)
Pulse rate  
Mean (Standard Deviation)
Unit of measure:  Beats/min
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
72.69  (11.22) 71.53  (10.86) 72.01  (10.62) 71.95  (10.92) 72.05  (10.91)
Total cholesterol  
Geometric Mean (Full Range)
Unit of measure:  mg/dL
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
165.38
(65.25 to 632.43)
164.96
(79.54 to 562.16)
164.38
(70.27 to 378.38)
165.97
(64.86 to 537.07)
165.17
(64.86 to 632.43)
Triglycerides  
Geometric Mean (Full Range)
Unit of measure:  mg/dL
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
163.66
(27.59 to 1913.50)
158.93
(10.68 to 3378.44)
162.30
(30.26 to 1438.24)
163.00
(35.60 to 2435.93)
161.96
(10.68 to 3378.44)
Free fatty acids  
Geometric Mean (Full Range)
Unit of measure:  mmol/L
Number Analyzed 826 participants 822 participants 824 participants 825 participants 3297 participants
0.83
(0.04 to 3.82)
0.80
(0.04 to 4.20)
0.83
(0.04 to 3.34)
0.81
(0.04 to 4.22)
0.82
(0.04 to 4.22)
1.Primary Outcome
Title Time From Randomisation to First Occurrence of a MACE, Defined as Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke
Hide Description Percentage of subjects experiencing a first event of a major adverse cardiovascular event (MACE), defined as cardiovascular (CV) death, non-fatal myocardial infarction (MI), or non-fatal stroke.
Time Frame Time from randomisation up to end of follow-up (scheduled at week 109)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects. As specified in the protocol, the two semaglutide dose arms (semaglutide 0.5 mg + semaglutide 1.0 mg) and the two placebo dose arms (placebo 0.5 mg + placebo 1.0 mg) were pooled for the analysis of this endpoint.
Arm/Group Title Semaglutide Placebo
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 1648 1649
Measure Type: Number
Unit of Measure: percentage of subjects
6.6 8.9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments The primary endpoint was analysed using a stratified Cox proportional hazards model with treatment group (semaglutide, placebo) as fixed factor. Assuming the same population MACE risk for the semaglutide and placebo groups (i.e., the population hazards ratio [HR] equals 1), a total minimum of 122 events were needed in order to have at least 90% power to ascertain that the upper two-sided 95% confidence limit for the HR was less than 1.8.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Non-inferiority of semaglutide versus placebo was considered to be confirmed if the upper limit of the two-sided 95% CI for the HR was below 1.8 or equivalent if the p-value for the one-sided test of: H0: HR ≥ 1.8 against Ha: HR <1.8 was less than 2.5% (or equivalent to 5% for a two-sided test).
Statistical Test of Hypothesis P-Value <0.0001
Comments The 'p-value' is for the two-sided Wald test of non-inferiority with limit 1.8.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.58 to 0.95
Estimation Comments Semaglutide/Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments A post hoc analysis of superiority of semaglutide versus placebo was performed based on the pre-specified Cox proportional hazard analysis using the two-sided Wald test of no difference, with treatment (semaglutide, placebo) as fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0167
Comments The 'p-value' is for the two-sided Wald test of no difference.
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.58 to 0.95
Estimation Comments Semaglutide/Placebo
2.Secondary Outcome
Title Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Outcome
Hide Description Percentage of subjects experiencing first occurrence of an expanded composite CV outcome (defined as either MACE, revascularisation [coronary and peripheral], unstable angina requiring hospitalisation or hospitalisation for heart failure)
Time Frame Time from randomisation up to end of follow-up (scheduled at week 109)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects. As specified in the protocol, the two semaglutide dose arms (semaglutide 0.5 mg + semaglutide 1.0 mg) and the two placebo dose arms (placebo 0.5 mg + placebo 1.0 mg) were pooled for the analysis of this endpoint.
Arm/Group Title Semaglutide Placebo
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 1648 1649
Measure Type: Number
Unit of Measure: percentage of subjects
12.1 16.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments Analysis was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0016
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.62 to 0.89
Estimation Comments Semaglutide/Placebo
3.Secondary Outcome
Title Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome
Hide Description Percentage of subjects experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as either MACE, revascularisation [coronary and peripheral], unstable angina requiring hospitalisation or hospitalisation for heart failure).
Time Frame Time from randomisation up to end of follow-up (scheduled at week 109)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects. As specified in the protocol, the two semaglutide dose arms (semaglutide 0.5 mg + semaglutide 1.0 mg) and the two placebo dose arms (placebo 0.5 mg + placebo 1.0 mg) were pooled for the analysis of this endpoint.
Arm/Group Title Semaglutide Placebo
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 1648 1649
Measure Type: Number
Unit of Measure: percentage of subjects
Cardiovascular death 1.6 1.9
Non-fatal MI 2.5 3.7
Non-fatal Stroke 1.5 2.5
Revascularisation 2.6 4.2
UAP requiring hospitalisation 1.1 1.3
Hospitalisation for heart failure 2.7 2.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments Analysis for CV death was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9181
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.65 to 1.48
Estimation Comments Semaglutide/Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments Analysis for non-fatal myocardial infarction was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1194
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.51 to 1.08
Estimation Comments Semaglutide/Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments Analysis for non-fatal stroke was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0438
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.61
Confidence Interval (2-Sided) 95%
0.38 to 0.99
Estimation Comments Semaglutide/Placebo
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments Analysis for revascularisation was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0027
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.50 to 0.86
Estimation Comments Semaglutide/Placebo
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments Analysis for 'unstable angina requiring hospitalisation' was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4914
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.47 to 1.44
Estimation Comments Semaglutide/Placebo
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments Analysis for hospitalisation for heart failure was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5735
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.11
Confidence Interval (2-Sided) 95%
0.77 to 1.61
Estimation Comments Semaglutide/Placcbo
4.Secondary Outcome
Title Time From Randomisation to First Occurrence of All-cause Death, Non-fatal MI, or Non-fatal Stroke
Hide Description Percentage of subjects experiencing a first occurrence of all-cause death, non-fatal MI, or non-fatal stroke.
Time Frame Time from randomisation up to end of follow-up (scheduled at week 109)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects. As specified in the protocol, the two semaglutide dose arms (semaglutide 0.5 mg + semaglutide 1.0 mg) and the two placebo dose arms (placebo 0.5 mg + placebo 1.0 mg) were pooled for the analysis of this endpoint.
Arm/Group Title Semaglutide Placebo
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 1648 1649
Measure Type: Number
Unit of Measure: percentage of subjects
7.4 9.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide, Placebo
Comments Analysis for all-cause death, non-fatal MI or non-fatal stroke was done by Cox proportional hazards model with treatment (semaglutide; placebo) as a fixed factor and stratified by all possible combinations of the three stratification factors used in the randomisation procedure (in total 9 levels).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0292
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.77
Confidence Interval (2-Sided) 95%
0.61 to 0.97
Estimation Comments Semaglutide/Placebo
5.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c)
Hide Description Estimated mean change from baseline in glycosylated haemoglobin (HbA1c) to last assessment in the trial during the treatment period.
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Least Squares Mean (Standard Error)
Unit of Measure: percentage of glycosylated haemoglobin
-1.09  (0.05) -1.41  (0.05) -0.44  (0.05) -0.36  (0.05)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -0.66
Confidence Interval (2-Sided) 95%
-0.80 to -0.52
Estimation Comments Sema 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -1.05
Confidence Interval (2-Sided) 95%
-1.19 to -0.91
Estimation Comments Sema 1.0 mg - Placebo 1.0 mg
6.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose
Hide Description Estimated mean change from baseline to last assessment in fasting plasma glucose in the trial during the treatment period.
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
-1.75  (0.12) -2.11  (0.12) -1.02  (0.12) -0.88  (0.12)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -0.72
Confidence Interval (2-Sided) 95%
-1.06 to -0.38
Estimation Comments Sema 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -1.22
Confidence Interval (2-Sided) 95%
-1.56 to -0.88
Estimation Comments Sema 1.0 mg - Placebo 1.0 mg
7.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight
Hide Description Estimated mean change from baseline to last assessment in body weight in the trial during the treatment period.
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects. As specified in the protocol, the two placebo dose arms (placebo 0.5 mg + placebo 1.0 mg) were pooled for the analysis of this endpoint.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg or 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment and the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 1649
Least Squares Mean (Standard Error)
Unit of Measure: kg
-3.57  (0.21) -4.88  (0.22) -0.62  (0.15)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo
Comments Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -2.95
Confidence Interval (2-Sided) 95%
-3.47 to -2.44
Estimation Comments Sema 0.5 mg - Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo
Comments Analysis was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -4.27
Confidence Interval (2-Sided) 95%
-4.78 to -3.75
Estimation Comments Semaglutide 1.0 mg - Placebo
8.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile
Hide Description Estimated ratio to baseline at week 104 during the treatment period in lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides).
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomised subjects.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
Total cholesterol (mg/dL) 0.97  (0.01) 0.97  (0.01) 1.00  (0.01) 0.99  (0.01)
HDL-cholesterol (mg/dL) 0.99  (0.01) 1.01  (0.01) 0.99  (0.01) 0.97  (0.01)
LDL-cholesterol (mg/dL) 0.97  (0.01) 0.98  (0.01) 1.01  (0.01) 0.99  (0.01)
Triglycerides (mg/dL) 0.93  (0.01) 0.92  (0.01) 0.96  (0.01) 0.98  (0.01)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for total cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0149
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.95 to 1.00
Estimation Comments Semaglutide 0.5 mg/Placebo 0.5 mg
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for total cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2580
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.97 to 1.01
Estimation Comments Semaglutide 1.0 mg/Placebo 1.0 mg
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for HDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8106
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.99 to 1.02
Estimation Comments Semaglutide 0.5 mg/Placebo 0.5 mg
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for HDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 1.04
Confidence Interval (2-Sided) 95%
1.02 to 1.06
Estimation Comments Semaglutide 1.0 mg/Placebo 1.0 mg
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for LDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0185
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.93 to 0.99
Estimation Comments Semaglutide 0.5 mg/Placebo 0.5 mg
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for LDL-cholesterol was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5996
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.96 to 1.03
Estimation Comments Semaglutide 1.0 mg/Placebo 1.0 mg
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for triglycerides was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1833
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.93 to 1.01
Estimation Comments Semaglutide 0.5 mg/Placebo 0.5 mg
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for triglycerides was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0009
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.89 to 0.97
Estimation Comments Semaglutide 1.0 mg/Placebo 1.0 mg
9.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio
Hide Description Estimated ratio to baseline in urinary albumin to creatinine ratio at week 104 during the treatment period.
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Least Squares Mean (Standard Error)
Unit of Measure: mg/g
1.02  (0.05) 0.91  (0.05) 1.32  (0.07) 1.29  (0.06)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for urinary albumin to creatinine ration was donne using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit. The response and its baseline value were log-transformed before analysis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.68 to 0.89
Estimation Comments Sema 0.5 mg / Placebo 0.5 mg
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for urinary albumin to creatinine ration was donne using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.71
Confidence Interval (2-Sided) 95%
0.62 to 0.81
Estimation Comments Sema 1.0 mg / Placebo 1.0 mg
10.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs
Hide Description Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (diastolic blood pressure and systolic blood pressure).
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Least Squares Mean (Standard Error)
Unit of Measure: mmHg
Diastolic blood pressure (mmHg) -1.37  (0.32) -1.57  (0.32) -1.42  (0.32) -1.71  (0.32)
Systolic blood pressure (mmHg) -3.44  (0.54) -5.37  (0.54) -2.17  (0.54) -2.78  (0.54)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for diastolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9205
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
-0.83 to 0.92
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for diastolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7477
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.14
Confidence Interval (2-Sided) 95%
-0.74 to 1.03
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for systolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0976
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -1.27
Confidence Interval (2-Sided) 95%
-2.77 to 0.23
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for systolic blood pressure was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -2.59
Confidence Interval (2-Sided) 95%
-4.09 to -1.08
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
11.Secondary Outcome
Title Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events
Hide Description Rates (event rate per 100 exposure years) of severe or blood glucose confirmed symptomatic hypoglycaemia defned as an episode that was severe according to the American diabetic association (ADA) classification or blood glucose (BG) confirmed by a PG value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
Time Frame Week 0 - 109
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomised subjects.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Measure Type: Number
Unit of Measure: Event rate per 100 exposure years
37.5 36.2 35.3 39.7
12.Secondary Outcome
Title Incidence During the Trial in Other Treatment Outcomes: Adverse Events
Hide Description Rates (event rate per 100 years of exposure) of treatment emergent adverse events.
Time Frame Weeks 0-109
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomised subjects.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Measure Type: Number
Unit of Measure: Event rate per 100 years of exposure
330.5 337.0 317.4 298.3
13.Secondary Outcome
Title Occurrence During the Trial in Other Treatment Outcomes: Anti-semaglutide Antibodies
Hide Description The percentage of subjects that tested positive for anti-semaglutide antibodies at any time point post-baseline during the trial, from week 0 to week 109.
Time Frame Weeks 0-109
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomised subjects
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822
Measure Type: Number
Unit of Measure: Percentage of subjects
1.4 2.3
14.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO)
Hide Description Estimated mean change from baseline to last assessment in the trial in patient reported outcomes (PRO). PRO questionnaire (SF-36v2TM) measured the individual overall health related quality of life namely bodily pain, general health, mental component summary, mental health, physical component summary, physical functioning, role-emotional, role-physical, social functioning and vitality. The PRO scores were transformed to a 0−100 scale with higher scores indicating greater health related quality of life.
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomised subjects.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Least Squares Mean (Standard Error)
Unit of Measure: Scores on a scale
Bodily pain 0.66  (0.35) 1.82  (0.35) 0.16  (0.35) 0.35  (0.35)
General health 1.66  (0.29) 2.55  (0.29) 0.78  (0.29) 1.13  (0.30)
Mental component summary 0.0  (0.35) 0.86  (0.35) -0.17  (0.35) -0.11  (0.35)
Mental health 0.48  (0.33) 1.08  (0.33) -0.14  (0.33) -0.31  (0.33)
Physical component summary 0.76  (0.28) 1.74  (0.28) 0.07  (0.28) 0.35  (0.28)
Physical functioning 0.42  (0.32) 1.12  (0.32) -0.38  (0.32) -0.37  (0.33)
Role-emotional 0.17  (0.42) 0.89  (0.42) -0.36  (0.42) -0.05  (0.42)
Role-physical 0.39  (0.34) 1.18  (0.35) -0.33  (0.35) 0.03  (0.35)
Social functioning -0.25  (0.35) 0.97  (0.35) -0.20  (0.36) -0.17  (0.36)
Vitality 0.29  (0.31) 1.55  (0.31) -0.04  (0.31) 0.35  (0.31)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for bodily pain was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3171
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.50
Confidence Interval (2-Sided) 95%
-0.48 to 1.47
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for bodily pain was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0031
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.47
Confidence Interval (2-Sided) 95%
0.50 to 2.45
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for general health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0350
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.87
Confidence Interval (2-Sided) 95%
0.06 to 1.69
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for general health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0007
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.42
Confidence Interval (2-Sided) 95%
0.60 to 2.24
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for mental component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7277
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.17
Confidence Interval (2-Sided) 95%
-0.79 to 1.13
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for mental component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0489
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
0.00 to 1.94
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for mental health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1860
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 0.61
Confidence Interval (2-Sided) 95%
-0.30 to 1.53
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for mental health was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0029
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.39
Confidence Interval (2-Sided) 95%
0.48 to 2.31
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for physical component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0833
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.68
Confidence Interval (2-Sided) 95%
-0.09 to 1.45
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for physical component summary was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.40
Confidence Interval (2-Sided) 95%
0.62 to 2.17
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 11 Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for physical functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0799
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
-0.10 to 1.69
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 12 Hide Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for physical functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0011
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.50
Confidence Interval (2-Sided) 95%
0.60 to 2.40
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 13 Hide Statistical Analysis 13
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for role emotional was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3717
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.53
Confidence Interval (2-Sided) 95%
-0.63 to 1.68
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 14 Hide Statistical Analysis 14
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for role emotional was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1136
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
-0.22 to 2.10
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 15 Hide Statistical Analysis 15
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for role physical was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1431
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.72
Confidence Interval (2-Sided) 95%
-0.24 to 1.67
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 16 Hide Statistical Analysis 16
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for role physical was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0197
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.14
Confidence Interval (2-Sided) 95%
0.18 to 2.11
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 17 Hide Statistical Analysis 17
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for social functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9223
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value -0.05
Confidence Interval (2-Sided) 95%
-1.03 to 0.93
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 18 Hide Statistical Analysis 18
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for social functioning was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0237
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.14
Confidence Interval (2-Sided) 95%
0.15 to 2.13
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Show Statistical Analysis 19 Hide Statistical Analysis 19
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for vitality was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4523
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 0.33
Confidence Interval (2-Sided) 95%
-0.53 to 1.19
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 20 Hide Statistical Analysis 20
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for vitality was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0064
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.20
Confidence Interval (2-Sided) 95%
0.34 to 2.07
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
15.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids)
Hide Description Estimated ratio to baseline at week 104 during the treatment period in lipid profile (free fatty acids).
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all randomised subjects.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
0.95  (0.02) 0.91  (0.01) 0.96  (0.02) 0.99  (0.02)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for free fatty acids was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7796
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.95 to 1.04
Estimation Comments Semaglutide 0.5 mg/Placebo 0.5 mg
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for free fatty acids was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment ratio
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.88 to 0.96
Estimation Comments Semaglutide 1.0 mg/Placebo 1.0 mg
16.Secondary Outcome
Title Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate)
Hide Description Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (pulse rate).
Time Frame Week 0, up to week 104
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full analysis set included all the randomised subjects.
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description:
Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks.
Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
Overall Number of Participants Analyzed 826 822 824 825
Least Squares Mean (Standard Error)
Unit of Measure: beats/min
2.12  (0.34) 2.41  (0.34) 0.09  (0.34) -0.07  (0.34)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Semaglutide 0.5 mg, Placebo 0.5 mg
Comments Analysis for pulse rate was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 2.02
Confidence Interval (2-Sided) 95%
1.07 to 2.98
Estimation Comments Semaglutide 0.5 mg - Placebo 0.5 mg
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Semaglutide 1.0 mg, Placebo 1.0 mg
Comments Analysis for pulse rate was done using a mixed model for repeated measurements with treatment (4 levels) and stratification (9 levels) as fixed factors and baseline value as covariate, all nested within visit.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 2.47
Confidence Interval (2-Sided) 95%
1.52 to 3.43
Estimation Comments Semaglutide 1.0 mg - Placebo 1.0 mg
Time Frame Adverse events from the first trial-related activity after the subject had signed the informed consent (week -2) until the end of the posttreatment follow-up period (week 109).
Adverse Event Reporting Description Safety was assessed using the full analysis set which included all randomised subjects. Subjects contributed to the evaluation as randomised.
 
Arm/Group Title Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Hide Arm/Group Description Subjects received once-weekly dose of semaglutide 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of semaglutide 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Semaglutide was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of placebo 0.5 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 0.5 mg was achieved after 4 weeks of treatment. Each subject was treated for 104 weeks. Subjects received once-weekly dose of placebo 1.0 mg as an add-on to their standard-of-care treatment. Injections were administered subcutaneously in the thigh, abdomen or upper arm, at any time of day irrespective of meals. The injections were to be administered on the same weekday during the trial. Placebo was initiated at a dose of 0.25 mg and was escalated (doubled) to 0.5 mg after 4 weeks. Hence the target dose of 1.0 mg was achieved after 8 weeks of treatment. Each subject was treated for 104 weeks.
All-Cause Mortality
Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo 0.5 mg Placebo 1.0 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   289/826 (34.99%)      276/822 (33.58%)      329/824 (39.93%)      298/825 (36.12%)    
Blood and lymphatic system disorders         
Anaemia  1  5/826 (0.61%)  5 4/822 (0.49%)  4 2/824 (0.24%)  2 2/825 (0.24%)  2
Haemorrhagic anaemia  1  1/826 (0.12%)  1 2/822 (0.24%)  2 0/824 (0.00%)  0 1/825 (0.12%)  1
Iron deficiency anaemia  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Leukocytosis  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Lymphadenopathy  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Lymphadenopathy mediastinal  1  0/826 (0.00%)  0 2/822 (0.24%)  2 1/824 (0.12%)  1 0/825 (0.00%)  0
Microcytic anaemia  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Splenic vein thrombosis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Splenomegaly  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Thrombocytopenia  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Cardiac disorders         
Acute coronary syndrome  1  4/826 (0.48%)  4 3/822 (0.36%)  3 1/824 (0.12%)  1 2/825 (0.24%)  2
Acute left ventricular failure  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Acute myocardial infarction  1  16/826 (1.94%)  21 13/822 (1.58%)  14 15/824 (1.82%)  15 27/825 (3.27%)  28
Angina pectoris  1  9/826 (1.09%)  9 9/822 (1.09%)  10 16/824 (1.94%)  17 12/825 (1.45%)  12
Angina unstable  1  13/826 (1.57%)  16 15/822 (1.82%)  18 19/824 (2.31%)  21 22/825 (2.67%)  23
Aortic valve disease  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Aortic valve stenosis  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Arrhythmia  1  1/826 (0.12%)  2 1/822 (0.12%)  1 1/824 (0.12%)  1 3/825 (0.36%)  3
Arteriosclerosis coronary artery  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 3/825 (0.36%)  3
Atrial fibrillation  1  14/826 (1.69%)  16 12/822 (1.46%)  15 20/824 (2.43%)  22 18/825 (2.18%)  19
Atrial flutter  1  1/826 (0.12%)  1 1/822 (0.12%)  1 4/824 (0.49%)  4 1/825 (0.12%)  1
Atrioventricular block  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Atrioventricular block complete  1  1/826 (0.12%)  1 0/822 (0.00%)  0 2/824 (0.24%)  2 3/825 (0.36%)  3
Atrioventricular block first degree  1  0/826 (0.00%)  0 1/822 (0.12%)  1 1/824 (0.12%)  1 0/825 (0.00%)  0
Atrioventricular block second degree  1  0/826 (0.00%)  0 2/822 (0.24%)  2 1/824 (0.12%)  1 1/825 (0.12%)  1
Bradycardia  1  1/826 (0.12%)  1 1/822 (0.12%)  1 2/824 (0.24%)  2 2/825 (0.24%)  2
Bundle branch block left  1  2/826 (0.24%)  2 1/822 (0.12%)  1 0/824 (0.00%)  0 3/825 (0.36%)  3
Bundle branch block right  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Cardiac arrest  1  5/826 (0.61%)  6 2/822 (0.24%)  2 3/824 (0.36%)  3 2/825 (0.24%)  3
Cardiac asthma  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Cardiac failure  1  10/826 (1.21%)  11 10/822 (1.22%)  10 7/824 (0.85%)  9 3/825 (0.36%)  4
Cardiac failure acute  1  2/826 (0.24%)  2 0/822 (0.00%)  0 4/824 (0.49%)  4 1/825 (0.12%)  2
Cardiac failure chronic  1  8/826 (0.97%)  8 4/822 (0.49%)  4 6/824 (0.73%)  6 3/825 (0.36%)  3
Cardiac failure congestive  1  21/826 (2.54%)  31 14/822 (1.70%)  17 15/824 (1.82%)  19 18/825 (2.18%)  21
Cardiac tamponade  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Cardiac ventricular thrombosis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Cardio-respiratory arrest  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Cardiogenic shock  1  0/826 (0.00%)  0 1/822 (0.12%)  1 3/824 (0.36%)  3 1/825 (0.12%)  1
Cardiomyopathy  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Cardiopulmonary failure  1  0/826 (0.00%)  0 1/822 (0.12%)  1 1/824 (0.12%)  1 0/825 (0.00%)  0
Cardiovascular insufficiency  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Congestive cardiomyopathy  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Coronary artery disease  1  11/826 (1.33%)  11 9/822 (1.09%)  9 5/824 (0.61%)  6 2/825 (0.24%)  3
Coronary artery insufficiency  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Coronary artery occlusion  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 1/825 (0.12%)  1
Coronary artery stenosis  1  7/826 (0.85%)  7 2/822 (0.24%)  2 4/824 (0.49%)  4 1/825 (0.12%)  1
Diabetic cardiomyopathy  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Hypertensive cardiomyopathy  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 1/825 (0.12%)  1
Ischaemic cardiomyopathy  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Left ventricular failure  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 1/825 (0.12%)  1
Mitral valve incompetence  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Myocardial infarction  1  4/826 (0.48%)  4 10/822 (1.22%)  10 9/824 (1.09%)  10 12/825 (1.45%)  14
Myocardial ischaemia  1  6/826 (0.73%)  6 2/822 (0.24%)  2 3/824 (0.36%)  3 2/825 (0.24%)  2
Myocarditis  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Nodal arrhythmia  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Pericardial effusion  1  2/826 (0.24%)  2 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Right ventricular failure  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Silent myocardial infarction  1  0/826 (0.00%)  0 2/822 (0.24%)  2 1/824 (0.12%)  1 0/825 (0.00%)  0
Sinus bradycardia  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Sinus node dysfunction  1  0/826 (0.00%)  0 2/822 (0.24%)  2 2/824 (0.24%)  2 0/825 (0.00%)  0
Supraventricular extrasystoles  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Supraventricular tachycardia  1  2/826 (0.24%)  2 2/822 (0.24%)  2 2/824 (0.24%)  2 1/825 (0.12%)  1
Tachycardia  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Tricuspid valve incompetence  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Ventricular arrhythmia  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Ventricular asystole  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Ventricular extrasystoles  1  1/826 (0.12%)  1 0/822 (0.00%)  0 1/824 (0.12%)  1 1/825 (0.12%)  1
Ventricular fibrillation  1  0/826 (0.00%)  0 2/822 (0.24%)  2 1/824 (0.12%)  1 2/825 (0.24%)  2
Ventricular hypokinesia  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Ventricular tachyarrhythmia  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Ventricular tachycardia  1  1/826 (0.12%)  1 8/822 (0.97%)  8 1/824 (0.12%)  2 2/825 (0.24%)  2
Atrial thrombosis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Bradyarrhythmia  1  0/826 (0.00%)  0 0/822 (0.00%)  0 2/824 (0.24%)  2 0/825 (0.00%)  0
Cor pulmonale acute  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Pulmonary valve stenosis  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Stress cardiomyopathy  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Congenital, familial and genetic disorders         
Phimosis  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Ear and labyrinth disorders         
Deafness neurosensory  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Otosclerosis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Tympanic membrane perforation  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Vertigo  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Endocrine disorders         
Goitre  1  0/826 (0.00%)  0 1/822 (0.12%)  1 1/824 (0.12%)  1 2/825 (0.24%)  2
Hyperthyroidism  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Inappropriate antidiuretic hormone secretion  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Thyroid mass  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Eye disorders         
Blindness  1  1/826 (0.12%)  1 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Cataract  1  1/826 (0.12%)  1 1/822 (0.12%)  1 1/824 (0.12%)  1 5/825 (0.61%)  6
Cataract cortical  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Cataract nuclear  1  1/826 (0.12%)  2 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Cystoid macular oedema  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Diabetic retinopathy  1  4/826 (0.48%)  4 2/822 (0.24%)  3 2/824 (0.24%)  2 4/825 (0.48%)  4
Diplopia  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Eyelid dermatochalasis  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Eyelid ptosis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Glaucoma  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 1/825 (0.12%)  1
Iridocyclitis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Macular fibrosis  1  0/826 (0.00%)  0 1/822 (0.12%)  1 1/824 (0.12%)  1 0/825 (0.00%)  0
Macular oedema  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Open angle glaucoma  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Optic ischaemic neuropathy  1  0/826 (0.00%)  0 2/822 (0.24%)  2 0/824 (0.00%)  0 0/825 (0.00%)  0
Retinal artery occlusion  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Retinal degeneration  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Retinal detachment  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 2/825 (0.24%)  2
Retinopathy haemorrhagic  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Vitreous haemorrhage  1  2/826 (0.24%)  2 2/822 (0.24%)  2 0/824 (0.00%)  0 0/825 (0.00%)  0
Amaurosis fugax  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Gastrointestinal disorders         
Abdominal mass  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Abdominal pain  1  2/826 (0.24%)  2 6/822 (0.73%)  6 2/824 (0.24%)  3 2/825 (0.24%)  2
Abdominal pain lower  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Abdominal pain upper  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Ascites  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 1/825 (0.12%)  1
Change of bowel habit  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Chronic gastritis  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Colitis  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Colitis ischaemic  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Colitis ulcerative  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Constipation  1  1/826 (0.12%)  1 1/822 (0.12%)  1 1/824 (0.12%)  1 0/825 (0.00%)  0
Diarrhoea  1  2/826 (0.24%)  2 6/822 (0.73%)  6 2/824 (0.24%)  2 1/825 (0.12%)  1
Diverticulum  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Diverticulum intestinal  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Duodenal ulcer  1  0/826 (0.00%)  0 1/822 (0.12%)  1 1/824 (0.12%)  1 1/825 (0.12%)  1
Duodenal ulcer haemorrhage  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Duodenitis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 1/825 (0.12%)  1
Enterocolitis haemorrhagic  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Epigastric discomfort  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Faeces discoloured  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Gastric disorder  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Gastric ileus  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Gastric polyps  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Gastric ulcer  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Gastric ulcer haemorrhage  1  2/826 (0.24%)  2 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Gastritis  1  1/826 (0.12%)  1 0/822 (0.00%)  0 2/824 (0.24%)  2 1/825 (0.12%)  1
Gastritis haemorrhagic  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Gastroduodenitis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Gastrointestinal haemorrhage  1  5/826 (0.61%)  5 1/822 (0.12%)  1 1/824 (0.12%)  1 4/825 (0.48%)  4
Gastrointestinal ischaemia  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Gastrooesophageal reflux disease  1  3/826 (0.36%)  3 3/822 (0.36%)  3 0/824 (0.00%)  0 1/825 (0.12%)  1
Hiatus hernia  1  0/826 (0.00%)  0 1/822 (0.12%)  1 2/824 (0.24%)  2 0/825 (0.00%)  0
Impaired gastric emptying  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Inguinal hernia  1  4/826 (0.48%)  4 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Intestinal haemorrhage  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Intestinal ischaemia  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Intestinal obstruction  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Large intestinal haemorrhage  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Large intestine polyp  1  0/826 (0.00%)  0 2/822 (0.24%)  2 1/824 (0.12%)  1 0/825 (0.00%)  0
Lower gastrointestinal haemorrhage  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Melaena  1  0/826 (0.00%)  0 1/822 (0.12%)  1 1/824 (0.12%)  1 0/825 (0.00%)  0
Mouth ulceration  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Nausea  1  0/826 (0.00%)  0 3/822 (0.36%)  3 1/824 (0.12%)  1 1/825 (0.12%)  1
Pancreatic cyst  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Pancreatitis  1  2/826 (0.24%)  2 0/822 (0.00%)  0 1/824 (0.12%)  1 4/825 (0.48%)  4
Pancreatitis acute  1  1/826 (0.12%)  1 1/822 (0.12%)  1 1/824 (0.12%)  1 2/825 (0.24%)  2
Peptic ulcer  1  1/826 (0.12%)  1 1/822 (0.12%)  1 1/824 (0.12%)  1 0/825 (0.00%)  0
Peritoneal haemorrhage  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Proctitis haemorrhagic  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Rectal prolapse  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Small intestinal obstruction  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 2/825 (0.24%)  2
Umbilical hernia  1  2/826 (0.24%)  2 0/822 (0.00%)  0 0/824 (0.00%)  0 2/825 (0.24%)  2
Upper gastrointestinal haemorrhage  1  2/826 (0.24%)  2 1/822 (0.12%)  1 2/824 (0.24%)  2 1/825 (0.12%)  1
Volvulus of small bowel  1  0/826 (0.00%)  0 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Vomiting  1  0/826 (0.00%)  0 3/822 (0.36%)  3 2/824 (0.24%)  2 2/825 (0.24%)  2
Diaphragmatic hernia  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Haematemesis  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 0/825 (0.00%)  0
Intestinal perforation  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
Oesophageal spasm  1  0/826 (0.00%)  0 0/822 (0.00%)  0 0/824 (0.00%)  0 1/825 (0.12%)  1
Pneumoperitoneum  1  1/826 (0.12%)  1 0/822 (0.00%)  0 0/824 (0.00%)  0 0/825 (0.00%)  0
General disorders         
Asthenia  1  0/826 (0.00%)  0 0/822 (0.00%)  0 1/824 (0.12%)  1 2/825 (0.24%)  2
Chest discomfort  1  1/826 (0.12%)  1 1/822 (0.12%)  1 1/824 (0.12%)  1 1/825 (0.12%)  1
Chest pain  1  1/826 (0.12%)  1 3/822 (0.36%)  3 5/824 (0.61%)  6 3/825 (0.36%)  3
Death  1  2/826 (0.24%)  2 3/822 (0.36%)  3 3/824 (0.36%)  3 2/825 (0.24%)  2
Device malfunction  1  1/826 (0.12%)  1 1/822 (0.12%)  1 0/824 (0.00%)  0 0/825 (0.00%)  0
Gait disturbance  1  0/826 (0.00%)  0 0/822 (0.00%)