ASCEND: A Study of Cardiovascular Events iN Diabetes

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine whether 100mg daily aspirin versus placebo and/or supplementation with 1 gram daily omega-3 fatty acids or placebo prevents serious vascular events (i.e. non-fatal heart attack, non-fatal stroke or transient ischaemic attack, or death from vascular causes) in patients with diabetes who are not known to have occlusive arterial disease and to assess the effects on serious bleeding or other adverse events.

Detailed Description
-----------------
The role of antiplatelet therapy (chiefly aspirin) for the secondary prevention of heart attacks and strokes is firmly established for many high-risk people with diagnosed arterial disease, and the proportional reductions in these cardiovascular events appear to be about one quarter, whether or not such patients have diabetes. But, most younger and middle-aged people with diabetes do not have manifest arterial disease - although they are still at significant cardiovascular risk - and yet few trials have tested aspirin in such individuals. As a result, there is substantial uncertainty about the role of aspirin for the prevention of heart attacks and strokes among apparently healthy people with diabetes, and only a small minority receives it. There is consistent evidence from observational studies of lower rates of cardiovascular disease (particularly cardiac and sudden death) in people with higher intakes, or higher blood levels, of fish oils (omega-3 fatty acids). Trials in people who have survived a heart attack have shown modest, but potentially worthwhile, reductions in coronary events. If ASCEND can reliably demonstrate that aspirin and/or fish oils safely reduce the risk of cardiovascular events and deaths in people with diabetes who do not have pre-existing arterial disease, then this would be relevant to some tens of millions of people world-wide (who are currently not receiving such therapy) and might save tens of thousands of lives each year. The initial results (published 2018) showed that aspirin prevented serious vascular events in patients with diabetes who did not already have cardiovascular disease, but it caused almost as many major bleeds and there was no effect on cancers. There was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. ASCEND will be conducting long-term follow-up for 20-years beyond the scheduled treatment period (which ended in 2017). We will collect relevant data from UK central health registries. This will be used to assess whether the balance of benefits versus hazards of aspirin observed within the main trial, relating to major vascular events such as heart attack or stroke, continue long-term or whether additional benefits emerge during longer-term follow-up. In addition ASCEND will use this long-term post-trial follow-up to investigate further whether low-dose aspirin might protect against cancer. The main cancer analyses is planned to take place  5-years after the end of the treatment period.

Official Title
-----------------
A Study of Cardiovascular Events iN Diabetes - A Randomized 2x2 Factorial Study of Aspirin Versus Placebo, and of Omega-3 Fatty Acid Supplementation Versus Placebo, for Primary Prevention of Cardiovascular Events in People With Diabetes

Conditions
-----------------
Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Aspirin
* Drug: Omega-3 Ethyl Esters
* Drug: Placebo Aspirin
* Drug: Placebo Omega-3 Ethyl Esters


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females with type 1 or type 2 diabetes mellitus. Aged ≥ 40 years. No previous history of vascular disease. No clear contra-indication to aspirin. No other predominant life-threatening medical problem. Exclusion Criteria: Definite history of myocardial infarction, stroke or arterial revascularisation procedure. Currently prescribed aspirin, warfarin or any other blood thinning medication.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aspirin + Omega-3 Ethyl Esters<br>Participants receive 100mg of aspirin once daily and 1g of omega-3 ethyl esters once daily. | Drug: Aspirin<br> <br> Drug: Omega-3 Ethyl Esters<br> <br> * Other names: Omacor;|
| Active Comparator: Aspirin + Placebo Omega-3 Ethyl Esters<br>Participants receive 100mg of aspirin once daily and placebo omega-3 ethyl esters once daily. | Drug: Aspirin<br> <br> Drug: Placebo Omega-3 Ethyl Esters<br> <br> |
| Active Comparator: Placebo Aspirin + Omega-3 Ethyl Esters<br>Participants receive placebo aspirin once daily and 1g of omega-3 ethyl esters once daily. | Drug: Omega-3 Ethyl Esters<br> <br> * Other names: Omacor;Drug: Placebo Aspirin<br> <br> |
| Active Comparator: Placebo Aspirin + Placebo Omega-3 Ethyl Esters<br>Participants receive placebo aspirin once daily and placebo omega-3 ethyl esters once daily. | Drug: Placebo Aspirin<br> <br> Drug: Placebo Omega-3 Ethyl Esters<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With First Occurrence of Any Serious Vascular Event (SVE) | The primary efficacy assessments involve intention-to-treat comparisons among all randomized participants of allocation to aspirin versus placebo and, separately, of omega-3 fatty acids versus placebo on the first occurrence of any Serious Vascular Event (SVE), defined as: non-fatal myocardial infarction; or non-fatal stroke (excluding confirmed intracranial hemorrhage) or TIA; or vascular death excluding confirmed intracranial hemorrhage (defined as International Classification of Diseases 10th revision [ICD-10] I00-52 or I63-99, i.e. excluding subarachnoid hemorrhage [I60], intracerebral hemorrhage [I61], and other non-traumatic intracranial hemorrhage [I62]). | Randomized treatment phase during a mean of 7.4 years | 
| Number of Participants With First Occurrence of Any Major Bleed (Aspirin Comparison Only) | The primary safety assessments involve intention-to-treat comparisons among all randomized patients of allocation to aspirin versus placebo on the first occurrence of any major bleed, defined as: any confirmed intracranial hemorrhage (including intracerebral, subarachnoid, subdural or any other intracranial hemorrhage); or sight-threatening eye bleeding; or any other serious bleeding episode. | Randomized treatment phase during a mean of 7.4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Combined End-point of Serious Vascular Events (SVEs) or Revascularizations | Secondary efficacy assessments involve intention-to-treat comparisons among all randomized participants of allocation to aspirin versus placebo and, separately, of omega-3 versus placebo on the first occurrence of the expanded vascular endpoint of SVE or revascularization (including coronary and non-coronary revascularizations). | Randomized treatment phase during a mean of 7.4 years | 
| Number of Participants With Any Incident Gastrointestinal (GI) Tract Cancer (Aspirin Comparison Only) | Secondary efficacy assessments of aspirin involve intention-to-treat comparisons during the scheduled treatment period among all randomized participants on the first occurrence of: Any incident gastrointestinal (GI) tract cancer (i.e. any GI cancer excluding pancreas and hepatobiliary), overall and after exclusion of the first three years of follow-up. | Randomized treatment phase during a mean of 7.4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes Mellitus, Cardiovascular Disease, Aspirin, Omega-3 fatty acids, Primary prevention, Randomized Controlled Trial, Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, n-3 fatty acid