Controlled Level EVERolimus in Acute Coronary Syndromes

Study Overview
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Brief Summary
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Acute myocardial infarction (AMI) constitutes the major cause of death in most nations and death rates and morbidity remain substantial in the years thereafter. Inflammation is a hallmark throughout the distinct stages of atherosclerotic lesion formation preceding AMI as well as at the time of plaque rupture and during the post-infarct repair phase. Harnessing its harmful consequences constitutes an attractive therapeutic approach to address this unmet medical need. The objectives of this study are to evaluate the effects of mTOR inhibition (everolimus) on infarct size, myocardial function and inflammation in patients with ST-Elevation Myocardial Infarction. The efficacy objectives are: (1° endpoint): To assess the effect of mTOR inhibition (everolimus) on myocardial infarct size as change from baseline (12-72 hours after percutaneous coronary intervention) to 30 days follow-up measured by MRI (Late Gadolinium Enhancement (LGE) for transmurality). (2° endpoint): To evaluate microvascular obstruction (MVO) as change from baseline (12-72 hours after percutaneous coronary intervention) to 30 days follow-up evaluated by MRI. (3° endpoints): Change of left ventricular volume from baseline (12-72 hours after percutaneous coronary intervention) to 30 days follow-up measured by MRI. Change of biomarkers from time of coronary angiography to 30 days follow-up including a time-course (AUC). Biomarkers comprise hs-TnT, NT-proBNP, hs-CRP, IL-6 and inflammatory biomarkers OPG, sRANKL, OPN and CCN1. The safety objectives are: To explore the effect of mTOR inhibition (everolimus) on several clinical and safety laboratory parameters including plasma lipid levels and blood count. This will be complemented by analysis of inflammatory cell subsets in coronary thrombi and peripheral blood (CD4+ T helper lymphocyte subsets, monocyte subsets).

Official Title
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Phase I-II Randomized Prospective Double-blind Multi-center Trial on the Effects of a Short Course of Oral Everolimus on Infarct Size, Left Ventricular Remodeling and Inflammation in Patients With Acute ST-Elevation Myocardial Infarction

Conditions
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Acute Coronary Syndromes

Intervention / Treatment
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* Drug: Everolimus
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Elevation Myocardial Infarction (STEMI) as defined by: ST-Elevation > 1mm in > 2 leads OR Novel left bundle branch block (LBBB) OR Posterior MI with ST-Depression > 1mm in > 2 leads Chest pain duration of > 10 minutes Primary Coronary Intervention (PCI) with drug-eluting stent (DES) within 24 hours of chest pain onset in the occluded culprit artery First Myocardial Infarction Occluded coronary artery at angiography specifically occlusion of one coronary vessel in the proximal third of either LAD, RCX or RCA, the mid segment of right coronary artery (RCA) or mid segment of a large left anterior descending (LAD) coronary artery, i.e. when the latter reaches the apex. Male and female patients 18 years to 90 years of age Signed informed consent Exclusion Criteria: Participation in another drug or stent trial Pregnant women or nursing mothers Mechanical complication during acute coronary syndrome Scheduled PCI for additional lesion within 30 days Multivessel disease Major elective surgery planned in trial period Malignancy (unless healed or remission > 5 years) Chronic infection (HIV, Tbc, empyema) Severely compromised renal function (GFR< 30 ml/min) Positive PCR Test for SARS-CoV-2 and/or at least one positive answer to questions regarding symptoms/contact related to COVID-19.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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 |
| --- | --- |
| Active Comparator: Everolimus<br>Everolimus p.o. for 5 days (d0=7.5 mg, d1=7.5 mg, d2=7.5 mg, d3=5 mg, d4=5mg) | Drug: Everolimus<br>* (d0=7.5 mg, d1=7.5 mg. d2=7.5 mg, d3=5 mg, d4=5mg)<br>|
| Placebo Comparator: Placebo<br>Placebo comparator with identical composition of tablets except everolimus | Drug: Placebo<br>* matched placebo tablets manufactured to be identical to verum tablets except content of everolimus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial infarct size measured by MRI | To assess the effect of mTOR inhibition (everolimus) on myocardial infarct size as measured by MRI (Late Gadolinium Enhancement (LGE) for infarct size (transmurality) at 12-72 h (baseline) and 30 days | Change from baseline at 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microvascular obstruction (MVO) measured by MRI | To evaluate microvascular obstruction (MVO) by MRI at 12-72 h (baseline) and 30 days | Change from baseline at 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Coronary Syndromes, ST-Elevation Myocardial Infarction, Infarct size, inflammation, everolimus