Vascular Effects of Alirocumab in Acute MI-Patients

Coronary Circulation Clinical Trial

— PACMAN-AMI  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03067844
• Other study ID #: 2016-01382
• Status: Completed
• Phase: Phase 3
• Start date: April 25, 2017
• Est. completion date: October 13, 2021

Study information

• Verified date: February 2022
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 294
• Est. completion date: October 13, 2021
• Est. primary completion date: October 13, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Atheroma; Myocardial
• Coronary Circulation
• Coronary Vessel
• Plaque, Atherosclerotic

Intervention

Drug:
• Alirocumab
Pre-filled auto-injector pen every second week, starting at day 1 and up to week 50

Locations

Country	Name	City	State
Austria	University Hospital Vienna (AKH)	Wien
Denmark	Rigshospitalet	Copenhagen
Netherlands	Radboud Univerity, Nijmegen Medical Centre	Nijmegen	Gelderland
Netherlands	Erasmus Thoraxcentre	Rotterdam
Switzerland	Basel University Hospital	Basel
Switzerland	Bern University Hospital Inselspital	Bern
Switzerland	Hopitaux Universitaires Geneve	Geneva
Switzerland	Stadtspital Triemli	Zurich
Switzerland	University Hospital Zurich USZ	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Denmark,  Netherlands,  Switzerland, 

References & Publications (13)

Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM; ODYSSEY COMBO II Investigators. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally — View Citation

Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 pati — View Citation

Koskinas KC, Ughi GJ, Windecker S, Tearney GJ, Räber L. Intracoronary imaging of coronary atherosclerosis: validation for diagnosis, prognosis and treatment. Eur Heart J. 2016 Feb 7;37(6):524-35a-c. doi: 10.1093/eurheartj/ehv642. Epub 2015 Dec 11. Review. — View Citation

Madder RD, Goldstein JA, Madden SP, Puri R, Wolski K, Hendricks M, Sum ST, Kini A, Sharma S, Rizik D, Brilakis ES, Shunk KA, Petersen J, Weisz G, Virmani R, Nicholls SJ, Maehara A, Mintz GS, Stone GW, Muller JE. Detection by near-infrared spectroscopy of — View Citation

Maehara A, Cristea E, Mintz GS, Lansky AJ, Dressler O, Biro S, Templin B, Virmani R, de Bruyne B, Serruys PW, Stone GW. Definitions and methodology for the grayscale and radiofrequency intravascular ultrasound and coronary angiographic analyses. JACC Card — View Citation

Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Dec 13;316(22):2373-2384. doi: 10.1001/jama.2016.16951. — View Citation

Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJP, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Honda S, Shishikura D, Scherer DJ, Borgman M, Brennan DM, Wolski K, Nissen SE. Effect of Evolocumab on Coronary Plaque Composition. J Am Coll Cardiol. 2018 Oct 23;72(17):2012-2021. doi: 10.1016/j.jacc.2018.06.078. — View Citation

Pu J, Mintz GS, Brilakis ES, Banerjee S, Abdel-Karim AR, Maini B, Biro S, Lee JB, Stone GW, Weisz G, Maehara A. In vivo characterization of coronary plaques: novel findings from comparing greyscale and virtual histology intravascular ultrasound and near-i — View Citation

Räber L, Taniwaki M, Zaugg S, Kelbæk H, Roffi M, Holmvang L, Noble S, Pedrazzini G, Moschovitis A, Lüscher TF, Matter CM, Serruys PW, Jüni P, Garcia-Garcia HM, Windecker S; IBIS 4 (Integrated Biomarkers and Imaging Study-4) Trial Investigators (NCT0096241 — View Citation

Räber L, Zanchin T, Baumgartner S, Taniwaki M, Kalesan B, Moschovitis A, Garcia-Garcia HM, Justiz J, Pilgrim T, Wenaweser P, Meier B, Jüni P, Windecker S. Differential healing response attributed to culprit lesions of patients with acute coronary syndrome — View Citation

Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducin — View Citation

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW; American College of Cardiology/American Heart Association Task Fo — View Citation

Tearney GJ, Regar E, Akasaka T, Adriaenssens T, Barlis P, Bezerra HG, Bouma B, Bruining N, Cho JM, Chowdhary S, Costa MA, de Silva R, Dijkstra J, Di Mario C, Dudek D, Falk E, Feldman MD, Fitzgerald P, Garcia-Garcia HM, Gonzalo N, Granada JF, Guagliumi G, — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

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