Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes

Study Overview
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Brief Summary
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This trial is conducted globally. The aim of the trial is to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes. The trial is event-driven, i.e. the maximum trial duration (up to max. 148 weeks) will depend on the accrual of major adverse cardiovascular events (MACE) in this trial and the remaining research programme. The incidence of MACE will be monitored throughout the trial which will be terminated according to plan when pre-specified stopping criteria are met.

Official Title
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A Long-term, Randomised, Double-blind, Placebo-controlled, Multinational, Multi-centre Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN™ 6 - Long-term Outcomes)

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: semaglutide
* Drug: semaglutide
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Men and women with type 2 diabetes mellitus - Age above or equal to 50 years at screening and clinical evidence of cardiovascular disease or age above or equal to 60 years at screening and subclinical evidence of cardiovascular disease - Anti-diabetic drug naïve, or treated with one or two oral antidiabetic drug (OADs), or treated with human Neutral Protamin Hagedorn (NPH) insulin or long-acting insulin analogue or pre-mixed insulin, both types of insulin either alone or in combination with one or two OADs - HbA1c above or equal to 7.0% at screening Exclusion Criteria: - Type 1 diabetes mellitus - Use of glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide, liraglutide, or other) or pramlintide within 90 days prior to screening - Use of any dipeptidyl peptidase 4 (DPP-IV) inhibitor within 30 days prior to screening - Treatment with insulin other than basal and pre-mixed insulin within 90 days prior to screening - except for short-term use in connection with intercurrent illness - Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (eg diabetes ketoacidosis) within 90 days prior to screening - History of chronic pancreatitis or idiopathic acute pancreatitis - Acute coronary or cerebro-vascular event within 90 days prior to randomisation - Currently planned coronary, carotid or peripheral artery revascularisation - Chronic heart failure New York Heart Association (NYHA) class IV - Personal or family history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma - Personal history of non-familial medullary thyroid carcinoma - Screening calcitonin above or equal to 50 ng/L

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide 0.5 mg<br> | Drug: semaglutide<br>* Once weekly doses of 0.5 mg semaglutide after an initial dose escalation step of 0.25 mg as an add-on to the standard-of-care treatment. Administered subcutaneously (s.c., under the skin)<br>|
| Experimental: Semaglutide 1.0 mg<br> | Drug: semaglutide<br>* Once weekly doses of 1.0 mg semaglutide after an initial dose escalation step of 0.25 mg followed by 0.5 mg dose escalation as an add-on to the standard-of-care treatment. Administered subcutaneously (s.c., under the skin)<br>|
| Placebo Comparator: Semaglutide placebo 0.5 mg<br> | Drug: placebo<br>* Once weekly doses volume-matched placebo, as an add-on to the standard-of-care treatment. Administered subcutaneously (s.c., under the skin).<br>|
| Placebo Comparator: Semaglutide placebo 1.0 mg<br> | Drug: placebo<br>* Once weekly doses volume-matched placebo, as an add-on to the standard-of-care treatment. Administered subcutaneously (s.c., under the skin).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Randomisation to First Occurrence of a MACE, Defined as Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke | 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 from randomisation up to end of follow-up (scheduled at week 109) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Patient Reported Outcome (PRO) | 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. | Week 0, up to week 104 | 
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile (Free Fatty Acids) | Estimated ratio to baseline at week 104 during the treatment period in lipid profile (free fatty acids). | Week 0, up to week 104 | 
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs (Pulse Rate) | Estimated mean change from baseline to last assessment in the trial during the treatment period in vital signs (pulse rate). | Week 0, up to week 104 | 
| Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Outcome | 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 from randomisation up to end of follow-up (scheduled at week 109) | 
| Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | 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 from randomisation up to end of follow-up (scheduled at week 109) | 
| Time From Randomisation to First Occurrence of All-cause Death, Non-fatal MI, or Non-fatal Stroke | Percentage of subjects experiencing a first occurrence of all-cause death, non-fatal MI, or non-fatal stroke. | Time from randomisation up to end of follow-up (scheduled at week 109) | 
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Glycosylated Haemoglobin (HbA1c) | Estimated mean change from baseline in glycosylated haemoglobin (HbA1c) to last assessment in the trial during the treatment period. | Week 0, up to week 104 | 
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Fasting Plasma Glucose | Estimated mean change from baseline to last assessment in fasting plasma glucose in the trial during the treatment period. | Week 0, up to week 104 | 
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Body Weight | Estimated mean change from baseline to last assessment in body weight in the trial during the treatment period. | Week 0, up to week 104 | 
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Lipid Profile | Estimated ratio to baseline at week 104 during the treatment period in lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides). | Week 0, up to week 104 | 
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Urinary Albumin to Creatinine Ratio | Estimated ratio to baseline in urinary albumin to creatinine ratio at week 104 during the treatment period. | Week 0, up to week 104 | 
| Change From Baseline to Last Assessment in the Trial in Other Treatment Outcomes: Vital Signs | 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). | Week 0, up to week 104 | 
| Incidence During the Trial in Other Treatment Outcomes: Hypoglycaemic Events | 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. | Week 0 - 109 | 
| Incidence During the Trial in Other Treatment Outcomes: Adverse Events | Rates (event rate per 100 years of exposure) of treatment emergent adverse events. | Weeks 0-109 | 
| Occurrence During the Trial in Other Treatment Outcomes: Anti-semaglutide Antibodies | 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. | Weeks 0-109 |