A Study of Cardiovascular Events iN Diabetes Plus

Study Overview
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Brief Summary
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ASCEND PLUS is testing whether, for people with type 2 diabetes who have not previously had a heart attack or stroke, regularly taking a tablet called semaglutide can safely help to reduce heart attacks, strokes, mini-strokes, the need for any procedures to unblock or bypass an artery to their heart, and the chance of dying because of vascular problems.

Detailed Description
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ASCEND PLUS aims to assess the effects of the GLP1 receptor agonist, oral semaglutide, on major adverse cardiovascular events in people with type 2 diabetes who have not previously suffered a heart attack or stroke. The study will be conducted using novel, streamlined methodology. Participants will be identified from centrally held routinely collected NHS healthcare datasets and invited to join the trial. There will be no physical sites, and all interactions with participants will be conducted directly using innovative patient-centred web-based technology, supplemented by telephone, video call contact and mailed letters. Study treatment will be mailed to participants. Information regarding serious adverse events and study outcomes relevant to patients with type 2 diabetes mellitus will be collected by regular linkage to UK National Health Service health records both during the scheduled treatment period and for the subsequent 20 years' long term follow-up after the scheduled treatment period. The trial design includes an active run-in phase, prior to randomisation, during which participants will be asked to take 4-weeks of active 3mg oral semaglutide followed by 4 to 8-weeks of active 7mg oral semaglutide daily. Participants who are randomised will be allocated to receive either 14mg oral semaglutide or matching placebo daily during the scheduled treatment period. There will be the opportunity to reduce the dose to 7mg or matching placebo if required. The scheduled treatment period, during which participants are requested to take the study treatment and complete follow-up assessments, is anticipated to continue until the required number of participants has experienced a primary outcome following randomisation. This is expected to occur at a median of approximately 5 years after randomisation.

Official Title
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A Study of Cardiovascular Events iN Diabetes Plus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Semaglutide Oral Tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged at least 55 years at the time of the Screening assessment Type 2 Diabetes Mellitus (based on self-reported medical history) Exclusion criteria: Myocardial Infarction Stroke Current or planned treatment with a GLP-1 RA Previous hypersensitivity to or intolerance of GLP-1 RA therapy Severe hypoglycaemia within the last six months or during run-in Symptomatic hypoglycaemia within the last month Currently under consideration to commence insulin Severe heart failure (NYHA class 4) Current or planned renal replacement therapy Unwilling to complete regular follow-up assessments Ongoing treatment for cancer or diagnosis with cancer (excluding non-melanoma skin cancer) in the last 2 years Type 1 or other type of diabetes (e.g. MODY) History of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma Currently breastfeeding or pregnant, or planning a pregnancy Any serious illness which is likely to limit survival or active participation for at least 5 years Current participation in a clinical trial with an unlicensed investigational medicinal product used to treat diabetes For participants taking thyroxine, lack of agreement to arrange a thyroid function test in the next 3 months and agree to regular testing throughout the trial Non-adherence to run-in treatment (i.e. reports taking the run-in tablets 'Never' or 'Only occasionally') Their doctor does not wish them to be randomised

Ages Eligible for Study
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Minimum Age: 55 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomised double-blind placebo-controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral semaglutide<br>14mg daily (option to reduce to 7mg daily) | Drug: Semaglutide Oral Tablet<br>* Oral semaglutide 14mg daily (option to reduce to 7mg daily)<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo oral tablet<br>* Placebo oral semaglutide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first occurrence of a Major Adverse Cardiovascular Events (MACE+) | MACE+ is an expanded composite, defined as: Death from cardiovascular disease Non-fatal myocardial infarction Non-fatal stroke Transient ischaemic attack Coronary revascularisation | Scheduled treatment period (anticipated median follow-up period of 5-years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first occurrence of a Major Adverse Cardiovascular Events (MACE) | MACE is a composite, defined as: Death from cardiovascular disease Non-fatal myocardial infarction Non-fatal stroke | Scheduled treatment period (anticipated median follow-up period of 5-years) |