Vascular Effects of Alirocumab in Acute MI-Patients

Phase 3

Completed

• Conditions: Coronary Circulation; Coronary Vessel; Atheroma; Myocardial
• Interventions: Drug: Alirocumab

• Registration Number: NCT03067844
• Lead Sponsor: Insel Gruppe AG, University Hospital Bern

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

Study Timeline

• Study First Submitted: 2017-02-24
• Study First Submitted QC: 2017-02-28
• Study First Posted: 2017-03-01
• Study Start: 2017-04-25
• Primary Completion: 2021-10-13
• Study Completion: 2021-10-13
• Status Verified: 2022-02
• Last Update Submitted: 2022-02-23
• Last Update Posted: 2022-02-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 294

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Alirocumab	Placebo, pre-filled auto-injector pen, every second week, starting at day 1 and up to week 50.
Alirocumab	Alirocumab	Alirocumab 150 mg/mL, pre-filled auto-injector pen, every second week, starting at day 1 and up to week 50.

Primary Outcome Measures

Name	Time	Method
Change in percent atheroma volume (PAV)	Baseline to week 52	Change in PAV by greyscale intravascular ultrasound (IVUS)

Secondary Outcome Measures

Name	Time	Method
Change in maximum LCBI in any 4-mm segment (Powered)	Baseline to week 52	Change in maximum LCBI in any 4-mm segment (maxLCBI4mm) as determined by NIRS
Change in hsCRP	Baseline to week 52	Change in hsCRP
Change in N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP)	Baseline to week 52	Change in NT-pro-BNP
Non-fatal myocardial infarction	Baseline to week 52	Any non-fatal myocardial infarction
Change in high sensitivity troponin T (hsTnT)	Baseline to week 52	Change in hsTnT
Death	Baseline to week 52	Any death, cardiac death
Change in LDL-cholesterol	Baseline to week 52	Change in LDL-cholesterol
Stroke	Baseline to week 52	Any ischemic stroke/transient ischemic attack
Change in total lipid-core burden index (LCBItotal)	Baseline to week 52	Change in LCBItotal as determined by near infrared spectroscopy (NIRS)
Change in minimal fibrous cap thickness (Powered)	Baseline to week 52	Change in minimal fibrous cap thickness as determined by optical coherence tomography (OCT)
Change in mean fibrous cap thickness	Baseline to week 52	Change in mean fibrous cap thickness as determined by OCT
Change in average angular extension (AAE) of macrophages	Baseline to week 52	Change in AAE of macrophages as determined by OCT
Change in normalized total atheroma volume (NTAV)	Baseline to week 52	Change in NTAV by IVUS
Change in further biomarkers	Baseline to week 52	Change in lipid and inflammatory markers and their association with indices of plaque progression/regression
Ischemia-driven coronary revascularization	Baseline to week 52	Any ischemia-driven coronary revascularization

Trial Locations

Locations (9)

Basel University Hospital; 🇨🇭 Basel, Switzerland

Hopitaux Universitaires Geneve; 🇨🇭 Geneva, Switzerland

University Hospital Zurich USZ; 🇨🇭 Zürich, Switzerland

Rigshospitalet; 🇩🇰 Copenhagen, Denmark

Radboud Univerity, Nijmegen Medical Centre; 🇳🇱 Nijmegen, Gelderland, Netherlands

Stadtspital Triemli; 🇨🇭 Zurich, Switzerland

University Hospital Vienna (AKH); 🇦🇹 Wien, Austria

Erasmus Thoraxcentre; 🇳🇱 Rotterdam, Netherlands

Bern University Hospital Inselspital; 🇨🇭 Bern, Switzerland