Clinical trial NCT03067844: Vascular Effects of Alirocumab in Acute MI-Patients
Official title: Effects of the PCSK9 Antibody AliroCuMab on Coronary Atherosclerosis in PatieNts With Acute Myocardial Infarction: A Serial, Multivessel, Intravascular Ultrasound, Near-Infrared Spectroscopy And Optical Coherence Tomography Imaging Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Coronary Vessel
Coronary Circulation
Atheroma; Myocardial
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Regeneron Pharmaceuticals
First posted: 2017-03-01
Enrollment: 294
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Coronary artery disease (CAD) is the most frequent cause of mortality in the industrialized world. Hypercholesterolemia is a major risk factor for the development and progression of CAD. While statins currently represent the first-line, gold-standard therapy for primary and secondary prevention of cardiovascular morbidity and mortality, nearly 50% of patients in Europe and Canada treated with statins do not achieve their target levels of low-density lipoprotein cholesterol (LDL-C) or cannot tolerate effective statin doses.

Recently, a growing number of studies of PCSK9 inhibitors in a wide spectrum of patients with hyperlipidemia on or off lipid-lowering therapy, familial hypercholesterolemia, and statin intolerance demonstrated consistent, profound, and sustained reductions in LDL-C with greater magnitude of reduction as compared with high-dose statin regimens. However, the effects of PCSK9 inhibition on coronary plaque morphology remain unknown.

This study will investigate the effect of the PCSK9 inhibitor alirocumab in patients with acute myocardial infarction undergoing percutaneous coronary intervention (PCI) in the infarct-related artery and receiving guideline-recommended high-intensity statin therapy. A serial, multivessel, intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography imaging study will be performed to determine the change in plaque volume at week 52. A total of 294 patients will be enrolled in the study and randomized in a 1:1 ratio to either alirocumab or placebo.

Detailed description: Substudies

* Biobank/drug monitoring, all sites
* Lipidomics (n=294), all sites
* Platelet Function (n=\~150), Bern
* Endothelial Function (n=\~150), Bern
* Neatherosclerosis (n=\~294), all sites
* Neutrophilic Extracellular Trap (NET), (n=\~50), Vienna
* OCT-NIRS/IVUS Matching Substudy (n=\~104), Bern
* Positron Emission Computed Tomography (PET-CT), (n=\~50), Copenhagen
* Shear Stress (n=\~294), London
* Quantitative Flow Ratio (QFR) (n=\~294), Bern

Eligibility criteria: Inclusion Criteria:

* Male or female, age ≥18 years at screening;
* Acute myocardial infarction: acute ST-segment elevation myocardial infarction (STEMI) with pain onset within ≤24h, or non-ST segment elevation myocardial infarction (NSTEMI), with at least one coronary segment (culprit lesion) requiring PCI;
* LDL-C ≥70 mg/dL (≥1.8 mmol/L) assessed prior to, or during PCI in patients who have been receiving any stable statin regimen within ≥ 4 weeks prior to enrollment; OR LDL-C ≥125 mg/dL (≥3.2 mmol/L) in patients who are statin-naïve or have not been on stable statin regimen for ≥ 4 weeks prior to enrollment;
* At least two major native coronary arteries ("target vessels") each meeting the following criteria for intracoronary imaging immediately following the qualifying PCI procedure: Angiographic evidence of \<50% reduction in lumen diameter by angiographic visual estimation;
* Target vessel deemed to be accessible to imaging catheters and suitable for intracoronary imaging in the proximal (50mm) segment ("target segment");
* Target vessel may not be a bypass (saphenous vein or arterial) graft or a bypassed native vessel;
* Target vessel must not have undergone previous PCI within the target segment;
* Target vessel is not candidate for intervention at the time of qualifying PCI or over the following 6 months in the judgment of the Investigator;
* Hemodynamic stability allowing the repetitive administration of nitroglycerine;
* Ability to understand the requirements of the study and to provide informed consent;
* Willingness to undergo follow-up intracoronary imaging.

Exclusion Criteria:

* Left-main disease, defined as ≥50% reduction in lumen diameter of the left main coronary artery by angiographic visual estimation;
* Three-vessel disease, defined as ≥70% reduction in lumen diameter of three major epicardial coronary arteries by angiographic visual estimation or in major branches of one or more of these arteries, irrespective of the localization (proximal 50mm or more distal localization) of the obstructive lesions;
* History of coronary artery bypass surgery;
* "Thrombolysis In Myocardial Infarction" (TIMI) flow \<2 of the infarct-related artery after PCI;
* Unstable clinical status (hemodynamic or electrical instability);
* Significant coronary calcification or tortuosity deemed to preclude IVUS, NIRS and OCT evaluation;
* Uncontrolled cardiac arrhythmia, defined as recurrent and symptomatic ventricular tachycardia or atrial fibrillation with rapid ventricular response not controlled by medications in the past 3 months prior to screening;
* Severe renal dysfunction, defined by estimated glomerular filtration rate \<30 ml/min/1.73m2;
* Active liver disease or hepatic dysfunction;
* Known intolerance to rosuvastatin OR known statin intolerance;
* Known allergy to contrast medium, heparin, aspirin, ticagrelor or prasugrel;
* Known sensitivity to any substances to be administered, including known statin intolerance;
* Patients who previously received alirocumab or other PCSK9 inhibitor;
* Patient who received cholesterol ester transfer protein inhibitors in the past 12 months prior to screening;
* Treatment with systemic steroids or systemic cyclosporine in the past 3 months;
* Known active infection or major hematologic, metabolic, or endocrine dysfunction in the judgment of the Investigator;
* Planned surgery within 12 months;
* Patients who will not be available for study-required visits in the judgment of the Investigator;
* Current enrollment in another investigational device or drug study;
* History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer;
* Estimated life expectancy less than 1 year;
* Female of childbearing potential (age \<50 years and last menstruation within the last 12 months), who did not undergo tubal ligation, ovariectomy or hysterectomy.

Primary outcomes:
measure: Change in percent atheroma volume (PAV)
timeFrame: Baseline to week 52
Secondary outcomes:
measure: Change in total lipid-core burden index (LCBItotal)
timeFrame: Baseline to week 52
measure: Change in maximum LCBI in any 4-mm segment (Powered)
timeFrame: Baseline to week 52
measure: Change in minimal fibrous cap thickness (Powered)
timeFrame: Baseline to week 52
measure: Change in mean fibrous cap thickness
timeFrame: Baseline to week 52
measure: Change in average angular extension (AAE) of macrophages
timeFrame: Baseline to week 52
measure: Change in normalized total atheroma volume (NTAV)
timeFrame: Baseline to week 52
measure: Change in LDL-cholesterol
timeFrame: Baseline to week 52
measure: Change in hsCRP
timeFrame: Baseline to week 52
measure: Change in high sensitivity troponin T (hsTnT)
timeFrame: Baseline to week 52
measure: Change in N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP)
timeFrame: Baseline to week 52
measure: Change in further biomarkers
timeFrame: Baseline to week 52
measure: Death
timeFrame: Baseline to week 52
measure: Non-fatal myocardial infarction
timeFrame: Baseline to week 52
measure: Ischemia-driven coronary revascularization
timeFrame: Baseline to week 52
measure: Stroke
timeFrame: Baseline to week 52
Other outcomes:
Locations:
city: Wien
country: Austria
facility: University Hospital Vienna (AKH)
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Nijmegen
country: Netherlands
facility: Radboud Univerity, Nijmegen Medical Centre
state: Gelderland
city: Rotterdam
country: Netherlands
facility: Erasmus Thoraxcentre
city: Basel
country: Switzerland
facility: Basel University Hospital
city: Bern
country: Switzerland
facility: Bern University Hospital Inselspital
city: Geneva
country: Switzerland
facility: Hopitaux Universitaires Geneve
city: Zurich
country: Switzerland
facility: Stadtspital Triemli
city: Zürich
country: Switzerland
facility: University Hospital Zurich USZ
Study officials:
affiliation: Bern Universitiy Hospital
name: Lorenz Raeber, Prof., MD
role: PRINCIPAL_INVESTIGATOR
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