A Trial Investigating the Cardiovascular Safety of Oral 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 investigate the cardiovascular safety of oral semaglutide in subjects with type 2 diabetes.

Official Title
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A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes

Conditions
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Diabetes, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: semaglutide
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female diagnosed with type 2 diabetes Age at least 50 years at screening and presence of cardiovascular disease, or age at least 60 years at screening and presence of at least one cardiovascular risk factor Exclusion Criteria: Current or previous (within 90 days prior to screening) treatment with any GLP-1 (glucagon-like peptide-1) receptor agonist, DPP-4 (dipeptidyl peptidase-4) inhibitor or pramlintide Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC) History of pancreatitis (acute or chronic) History of major surgical procedures involving the stomach potentially affecting absorption of trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) Subjects presently classified as being in New York Heart Association (NYHA) Class IV heart failure Planned coronary, carotid or peripheral artery revascularisation known on the day of screening Any of the following: myocardial infarction, stroke or hospitalisation for unstable angina or transient ischaemic attack within the past 60 days prior to screening Chronic or intermittent hemodialysis or peritoneal dialysis or severe renal impairment (corresponding to eGFR (glomerular filtration rate, estimated) below 30 mL/min/1.73 m^2) History or presence of malignant neoplasms within the last 5 years (except basal and squamous cell skin cancer and carcinoma in situ)

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: Oral semaglutide<br> | Drug: semaglutide<br>* For oral use once daily.<br>|
| Placebo Comparator: Placebo<br> | Drug: placebo<br>* For oral use once daily.<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 Major Adverse Cardiovascular Event (MACE) Composite Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction or Non-fatal Stroke | Number of participants experiencing a first event of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From Randomisation to First Occurrence of an Expanded Composite Cardiovascular Endpoint Consisting of: Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, UAP Requiring Hospitalisation or Hospitalisation for Heart Failure | Participants experiencing first occurrence of an expanded composite CV endpoint [defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, UAP (unstable angina pectoris) requiring hospitalisation or heart failure requiring hospitalisation] are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | 
| Time From Randomisation to First Occurrence of Each of the Individual Components in the Expanded Composite Cardiovascular Endpoint | Participants experiencing an event onset for each individual component of the expanded composite cardiovascular outcomes (defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalisation or heart failure requiring hospitalisation) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | 
| Time From Randomisation to First Occurrence of a Composite Endpoint Consisting of: All-cause Death, Non-fatal Myocardial Infarction or Nonfatal Stroke | Participants experiencing first occurrence of a composite CV endpoint (defined as all-cause death, non-fatal myocardial infarction or nonfatal stroke) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | 
| Time From Randomisation to First Occurrence of Fatal or Non-fatal Myocardial Infarction | Number of participants experiencing a first event of a fatal or non-fatal myocardial infarction are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | 
| Time From Randomisation to First Occurrence of Fatal or Non-fatal Stroke | Number of participants experiencing a first event of a fatal or non-fatal stroke are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Maximum treatment duration is dependent on event rates and is estimated to be no longer than 19 months + 5 weeks of follow-up period. | 
| Time From Randomisation to All-cause Death | Number of all-cause deaths in the study are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 5 weeks of follow-up period. | 
| Time to First AE Leading to Permanent Trial Product Discontinuation | Number of participants who permanently discontinued trial product in ths study are presented. Results are based on the on-treatment observation period which starts at the date of first dose on trial product; ends on last date on trial product +38 days (ascertainment window). | Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window. | 
| Number of Serious Adverse Events | Number of serious adverse events were recorded from week 0 to week 87 in the study. Results are based on the on-treatment observation period which started at the date of first dose on trial product and ended on last date on trial product +38 days (ascertainment window). | Maximum treatment duration is dependent on event rates and is expected to be no longer than 19 months + 38 days of ascertainment window. | 
| Change in Eye Examination Category | Participants with eye examination findings, normal, abnormal non clinically significant (NCS) and abnormal clinically significant (CS) at baseline (week -3) and end of treatment visit (week 83) are presented. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Week -3, End of treatment | 
| Change in Pulse Rate | Change from baseline (week 0) in pulse rate measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window). | Week 0, End of treatment | 
| Change in Systolic and Diastolic Blood Pressure | Change from baseline (week 0) in systolic and diastolic blood pressure measured at the end of treatment visit (week 83) is reported. Results are based on the on-treatment observation period which started at the date of first dose on trial product, ended on last date on trial product +38 days (ascertainment window). | Week 0, End of treatment | 
| Change in Glycosylated Haemoglobin (HbA1c) | Change from baseline (week 0) in HbA1c measured at the end of treatment visit (week 83) is reported. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Week 0, End of treatment | 
| Change in Body Weight | Change from baseline (week 0) in body weight measured at the end of treatment visit (week 83) is reported. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Week 0, End of treatment | 
| Change in Total Cholesterol - Ratio to Baseline | Change from baseline (week 0) in total cholesterol (mmol/L) at the end of treatment (week 83) visit is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Week 0, End of treatment | 
| Change in LDL-cholesterol - Ratio to Baseline | Change from baseline (week 0) in LDL cholesterol (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Week 0, End of treatment | 
| Change in HDL-cholesterol - Ratio to Baseline | Change from baseline (week 0) in HDL cholesterol (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Week 0, End of treatment | 
| Change in Triglycerides - Ratio to Baseline | Change from baseline (week 0) in triglycerides (mmol/L) at end of treatment visit (week 83) is presented as ratio to baseline. Results are based on the in-trial observation period which started at the date of randomisation, included the period after permanent trial product discontinuation, if any and ended at the date of the follow-up visit regardless of adherence to treatment. | Week 0, End of treatment |