Clinical trial NCT01529554: Controlled Level EVERolimus in Acute Coronary Syndromes
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Coronary Syndromes
Keywords: Acute Coronary Syndromes
ST-Elevation Myocardial Infarction
Infarct size
inflammation
everolimus
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
name: Novartis
First posted: 2012-02-09
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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. (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. (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. (3° endpoints):

   1. Change of left ventricular volume from baseline (12-72 hours after percutaneous coronary intervention) to 30 days follow-up measured by MRI.
   2. 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).


Eligibility criteria: Inclusion Criteria:

1. 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
2. Chest pain duration of \> 10 minutes
3. Primary Coronary Intervention (PCI) with drug-eluting stent (DES) within 24 hours of chest pain onset in the occluded culprit artery
4. First Myocardial Infarction
5. 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.
6. Male and female patients 18 years to 90 years of age
7. Signed informed consent

Exclusion Criteria:

1. Participation in another drug or stent trial
2. Pregnant women or nursing mothers
3. Mechanical complication during acute coronary syndrome
4. Scheduled PCI for additional lesion within 30 days
5. Multivessel disease
6. Major elective surgery planned in trial period
7. Malignancy (unless healed or remission \> 5 years)
8. Chronic infection (HIV, Tbc, empyema)
9. Severely compromised renal function (GFR\< 30 ml/min)
10. Positive PCR Test for SARS-CoV-2 and/or at least one positive answer to questions regarding symptoms/contact related to COVID-19.

Primary outcomes:
measure: Myocardial infarct size measured by MRI
timeFrame: Change from baseline at 30 days
Secondary outcomes:
measure: Microvascular obstruction (MVO) measured by MRI
timeFrame: Change from baseline at 30 days
Other outcomes:
measure: Left ventricular volume measured by MRI
timeFrame: Change from baseline at 30 days
measure: Biomarkers
timeFrame: Change from baseline at 30 days including time course
Locations:
city: Bad Nauheim
country: Germany
facility: Kerckhoff-Klinik, Department of Cardiology
city: Berlin
country: Germany
facility: University Hospital Chartié
city: Düsseldorf
country: Germany
facility: University Hospital Duesseldorf
city: Mainz
country: Germany
facility: University Hospital Mainz
city: Bern
country: Switzerland
facility: University Hospital Bern
city: Geneva
country: Switzerland
facility: University Hospital Geneva
city: Lugano
country: Switzerland
facility: Cardiocentro Ticino
city: Zurich
country: Switzerland
facility: University Hospital Zurich
Study officials:
affiliation: UniversityHospitalZurich
name: Frank Ruschitzka, Professor
role: STUDY_DIRECTOR
References:
citation: Stahli BE, Klingenberg R, Heg D, Branca M, Manka R, Kapos I, Muggler O, Denegri A, Kesterke R, Berger F, Stehli J, Candreva A, von Eckardstein A, Carballo D, Hamm C, Landmesser U, Mach F, Moccetti T, Jung C, Kelm M, Munzel T, Pedrazzini G, Raber L, Windecker S, Templin C, Matter CM, Luscher TF, Ruschitzka F. Mammalian Target of Rapamycin Inhibition in Patients With ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol. 2022 Nov 8;80(19):1802-1814. doi: 10.1016/j.jacc.2022.08.747. Epub 2022 Aug 29.
citation: Klingenberg R, Stahli BE, Heg D, Denegri A, Manka R, Kapos I, von Eckardstein A, Carballo D, Hamm CW, Vietheer J, Rolf A, Landmesser U, Mach F, Moccetti T, Jung C, Kelm M, Munzel T, Pedrazzini G, Raber L, Windecker S, Matter CM, Ruschitzka F, Luscher TF. Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS) - A phase II, randomized, double-blind, multi-center, placebo-controlled trial. Am Heart J. 2022 May;247:33-41. doi: 10.1016/j.ahj.2022.01.010. Epub 2022 Jan 28.