A Heart Disease Study of Semaglutide in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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The researchers are doing this study to look whether the type 2 diabetes medicine, semaglutide, has a positive effect on heart disease. Participants will either get semaglutide tablets or placebo tablets (dummy medicine) - which treatment is decided by chance. Participants must take one tablet with water every morning on an empty stomach and not eat or drink anything for at least 30 minutes. The study will last for about 3.5-5 years. Participants will have up to 25 clinic visits and 1 phone call with the study doctor. Women cannot be in the study if pregnant, breast-feeding or if they plan to become pregnant during the study period.

Official Title
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Semaglutide Cardiovascular Outcomes Trial in Patients With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

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: Male or female, age equal to or above 50 years at the time of signing informed consent Diagnosed with type 2 diabetes mellitus HbA1c 6.5% - 10.0% (47 - 86 mmol/mol) (both inclusive) (latest available and no more than 30 days old local laboratory assessment based on medical records or point of care measurement) At least one of the below conditions (a-d): a) Coronary heart disease defined as at least one of the following: i. Prior myocardial infarction ii. Prior coronary revascularisation procedure iii. 50% or above stenosis in coronary artery documented by cardiac catheterisation, computerized tomography coronary angiography iv. Coronary heart disease with ischaemia documented by stress test with any imaging modality b) Cerebrovascular disease defined as at least one of the following: i. Prior stroke ii. Prior carotid artery revascularisation procedure iii.50% or above stenosis in carotid artery documented by X-ray angiography, magnetic resonance angiography, computerized tomography angiography or Doppler ultrasound c) Symptomatic peripheral artery disease (PAD) defined as at least one of the following: i. Intermittent claudication with an Ankle-brachial index (ABI) below 0.85 at rest ii. Intermittent claudication with a 50% or above stenosis in peripheral artery (excluding carotid) documented by X-ray angiography, magnetic resonance angiography, computerized tomography angiography or Doppler ultrasound iii. Prior peripheral artery (excluding carotid) revascularization procedure iv. Lower extremity amputation at or above ankle due to atherosclerotic disease (excluding e.g. trauma or osteomyelitis) d) Chronic kidney disease defined as: i. eGFR below 60 mL/min/1.73 m^2 (based on medical records using latest available and no more than 6 months old assessment) Exclusion Criteria: 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 Heart failure presently classified as being in New York Heart Association Class IV Treatment with any glucagon-like peptide-1 receptor agonist within 30 days before screening

Ages Eligible for Study
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Minimum Age: 50 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: Oral semaglutide<br>One tablet daily for 3.5 to 5 years | Drug: Semaglutide<br>* Increasing doses (3 mg/7 mg/14 mg) of semaglutide tablets to be taken with water at the same time every morning in a fasting state<br>|
| Placebo Comparator: Placebo<br>One tablet daily for 3.5 to 5 years | Drug: Placebo (semaglutide)<br>* Placebo tablets to be taken with water at the same time every morning in a fasting state<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 major adverse cardiovascular event (MACE), a composite endpoint consisting of: cardiovascular (CV) death/non-fatal myocardial infarction/non-fatal stroke | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) (trial is event driven) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first occurrence of a composite endpoint | Time to first occurrence of a composite endpoint consisting of: CV death/renal death/onset of persistent 50% or more reduction in estimated glomerular filtration rate (eGFR) (chronic kidney disease - epidemiology collaboration (CKD-EPI)) (compared with baseline)/onset of persistent eGFR (CKD-EPI) below 15 mL/min/1.73 m^2/initiation of chronic renal replacement therapy (dialysis or kidney transplantation). Unit of assessment: Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to occurrence of CV death | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of major adverse limb events (MALE), a composite endpoint consisting of: acute limb ischemia hospitalisation/chronic limb ischemia hospitalisation | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of an expanded MACE composite endpoint consisting of: CV death/non-fatal myocardial infarction/ non-fatal stroke/coronary revascularisation/unstable angina requiring hospitalisation | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of a composite heart failure endpoint consisting of: CV death/heart failure requiring hospitalisation/urgent heart failure visit | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of a composite CKD endpoint | Time to first occurrence of a composite CKD endpoint consisting of: renal death/onset of persistent 50% or more reduction in eGFR (CKD-EPI)/onset of persistent eGFR (CKD-EPI) below 15 mL/min/1.73 m^2/initiation of chronic renal replacement therapy (dialysis or kidney transplantation). Unit of assessment: Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to occurrence of all-cause death | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of non-fatal myocardial infarction (MI) | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of non-fatal stroke | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of heart failure requiring hospitalisation | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of urgent heart failure visit | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of coronary revascularisation | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of unstable angina requiring hospitalisation | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to occurrence of renal death | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of onset of persistent 50% or more reduction in eGFR | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of onset of persistent eGFR (CKD-EPI) below 15 mL/min/1.73 m^2 | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of initiation of chronic renal replacement therapy (dialysis or kidney transplantation) | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of a composite endpoint consisting of: all-cause death/non-fatal myocardial infarction/non-fatal stroke | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of acute limb ischemia | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of chronic limb ischemia | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Annual rate of change in eGFR (CKD-EPI) (total eGFR slope) | ml/min/1.73 m^2 per year | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Change in glycosylated haemoglobin (HbA1c) | Percent points | From randomisation (week 0) to 2 years | 
| Change in body weight | Kilograms | From randomisation (week 0) to 2 years | 
| Number of severe hypoglycaemic episodes | Number of events | From randomisation (week 0) to end-of-trial (up to 61 months or more) | 
| Time to first occurrence of a severe hypoglycaemic episode | Months | From randomisation (week 0) to end-of-trial (up to 61 months or more) |