Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity

Study Overview
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Brief Summary
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The researchers are doing the study to see if semaglutide may reduce the risk of having cardiovascular events in patients with overweight or obesity and with prior cardiovascular disease. The participant will either get semaglutide (active medicine) or placebo (dummy medicine). Which treatment the participants get is decided by chance. The participant's chance of getting semaglutide or placebo is the same. The participant will get the study medicine in a pen. The participants will need to use the pen to inject the study medicine in a skinfold once a week. The study will last for about 2.5 to 5 years. Participants will have up to 25 clinic visits with the study doctor.

Official Title
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SELECT - Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity

Conditions
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Overweight, Obesity

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Placebo (semaglutide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial Male or female, age greater than or equal to 45 years at the time of signing informed consent Body mass index (BMI) greater than or equal to 27 kg/m^2 Have established cardiovascular (CV) disease as evidenced by at least one of the following: prior myocardial infarction; prior stroke (ischemic or haemorrhagic stroke); or symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) less than 0.85 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease Exclusion Criteria: Cardiovascular-related: Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Presently classified as being in New York Heart Association (NYHA) Class IV heart failure Glycaemia-related: HbA1c greater than or equal to 48 mmol/mol (6.5 %) as measured by the central laboratory at screening History of type 1 or type 2 diabetes (history of gestational diabetes is allowed) Treatment with glucose-lowering agents within 90 days before screening Treatment with any glucagon-like-peptide-1 receptor agonist (GLP-1 RA) within 90 days before screening General safety: History or presence of chronic pancreatitis Presence of acute pancreatitis within the past 180 days prior to the day of screening Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma End stage renal disease or chronic or intermittent haemodialysis or peritoneal dialysis Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed Severe psychiatric disorder which in the investigator's opinion could compromise compliance with the protocol Known or suspected hypersensitivity to trial products or related products Previous participation in this trial. Participation is defined as randomisation Receipt of any investigational medicinal product within 30 days before screening Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method Any disorder, unwillingness or inability, which in the investigator's opinion, might jeopardise the participant's safety or compliance with the protocol

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide<br>Participants will receive semaglutide as an adjunct to standard-of-care. Estimated trial duration for an individual subject is from 31 to 59 months. | Drug: Semaglutide<br>* Semaglutide will be injected into a skin fold, in the stomach, thigh or upper arm once a week at the same day of the week (to the extent possible) throughout the trial. Subjects will start semaglutide treatment at 0.24 mg; dose will gradually be increased every 4 weeks up to 2.4 mg.<br>|
| Placebo Comparator: Placebo (semaglutide)<br>Participants will receive placebo (semaglutide) as an adjunct to standard-of-care. Estimated trial duration for an individual subject is from 31 to 59 months. | Drug: Placebo (semaglutide)<br>* Placebo will be injected into a skin fold, in the stomach, thigh or upper arm once a week at the same day of the week (to the extent possible) throughout the trial. Participants will receive placebo at an equivalent dose to semaglutide.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of a composite endpoint consisting of: cardiovascular (CV) death, non-fatal myocardial infarction, or non-fatal stroke | Measured in months | 0-59 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to CV death | Measured in months | 0-59 months | 
| Time to all-cause death | Measured in months | 0-59 months | 
| Time to first occurrence of an expanded composite CV endpoint consisting of: CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation or unstable angina requiring hospitalisation | Measured in months | 0-59 months | 
| Time to first occurrence of a composite heart failure endpoint consisting of: heart failure hospitalisation, urgent heartfailure visit or CV death | Measured in months | 0-59 months | 
| Time to first occurrence of a composite endpoint consisting of: all-cause death, non-fatal myocardial infarction, or non-fatal stroke | Measured in months | 0-59 months | 
| Time to first occurrence of non-fatal myocardial infarction | Measured in months | 0-59 months | 
| Time to first occurrence of non-fatal stroke | Measured in months | 0-59 months | 
| Time to first occurrence of coronary revascularisation | Measured in months | 0-59 months | 
| Time to first occurrence of unstable angina requiring hospitalisation | Measured in months | 0-59 months | 
| Time to first occurrence of heart failure hospitalisation or urgent heart failure visit | Measured in months | 0-59 months | 
| Time to first occurrence of HbA1c greater than or equal to 48 mmol/mol (6.5%) | Measured in months | 0-59 months | 
| Time to first occurrence of a 5-component composite nephropathy endpoint | Measured in months. A 5-component composite nephropathy endpoint consists of: onset of persistent macroalbuminuria (UACR above 300 mg/g), persistent 50% reduction in estimated Glomerular Filtration Rate (eGFR) compared with baseline (randomisation), onset of persistent eGFR less than 15 ml/min/1.73m^2, initiation of chronic renal replacement therapy (dialysis or transplantation) or renal death. | 0-59 months | 
| Time to HbA1c greater than or equal to 39 mmol/mol (5.7%) for subjects with a screening HbA1c less than 39 mmol/mol (5.7%) | Measured in months | 0-59 months | 
| Subjects with HbA1c less than 39 mmol/mol (5.7%) at each visit where HbA1c is assessed for subjects with a screening HbA1c greater than or equal to 39 mmol/mol (5.7%) | Proportion of subjects | 0-59 months | 
| Change in systolic blood pressure | Measured in mm Hg | Week 0, year 2 | 
| Change in diastolic blood pressure | Measured in mm Hg | Week 0, year 2 | 
| Change in pulse | Measured in beats per minute | Week 0, year 2 | 
| Change in High sensitivity C-Reactive Protein (hsCRP) | Measured in mg/dL | Week 0, year 2 | 
| Change in total cholesterol | Measured in mg/dL | Week 0, year 2 | 
| Change in high density lipoprotein (HDL) cholesterol | Measured in mg/dL | Week 0, year 2 | 
| Change in low density lipoprotein (LDL) cholesterol | Measured in mg/dL | Week 0, year 2 | 
| Change in triglycerides | Measured in mg/dL | Week 0, year 2 | 
| Change in body weight | Measured in % | Week 0, year 2 | 
| Change in waist circumference | Measured in cm | Week 0, year 2 | 
| Change in EuroQol five dimensions five level (EQ-5D-5L) questionnaire | The EQ-5D-5L questionnaire will be used to estimate the impact on subjects' health-related quality of life and provides a description of subjects' problems by dimensions (descriptive system), a score for overall self-rated health (visual analogue scale [VAS]) as well as an index score (EQ-5D-5L index). EQ-5D index score range: 0 to 1 and EQ-5D-VAS: range 0 to 100. A higher score indicates better self reported health status. | Week 0, year 2 | 
| Change in total score weight related sign and symptom measure | The weight related sign and symptom measure assesses the presence and bother associated with weight-related symptoms using a self-rated VAS. It is a tool to assess the multifaceted aspects of obesity on symptom experience in subjects with overweight or obesity. | Week 0, year 2 | 
| Change in haemoglobin A1c (HbA1c) | Measured in % | Screening (up to 3 weeks before randomisation at week 0), week 104 | 
| Change in HbA1c | Measured in mmol/mol | Screening (up to 3 weeks before randomisation at week 0), week 104 |