Vascular Effects of Alirocumab in Acute MI-Patients

NCT03067844 | Completed Phase 3 DMC

• 1 other identifier: 2016-01382
• Study Type: interventional
• Target: 294
• Locations: 4 countries
• Sites: 9

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.

Conditions

Coronary Vessel; Coronary Circulation; Atheroma; Myocardial

Outcome Measures

Primary Outcomes (1)

• Change in percent atheroma volume (PAV)

  Change in PAV by greyscale intravascular ultrasound (IVUS)

  Baseline to week 52

Secondary Outcomes (15)

• Change in total lipid-core burden index (LCBItotal)

  Baseline to week 52

• Change in maximum LCBI in any 4-mm segment (Powered)

  Baseline to week 52

• Change in minimal fibrous cap thickness (Powered)

  Baseline to week 52

• Change in mean fibrous cap thickness

  Baseline to week 52

• Change in average angular extension (AAE) of macrophages

  Baseline to week 52

Study Arms (2)

Alirocumab

EXPERIMENTAL

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

Drug: Alirocumab

Placebo

PLACEBO COMPARATOR

Placebo, pre-filled auto-injector pen, every second week, starting at day 1 and up to week 50.

Drug: Alirocumab

Interventions

Alirocumab DRUG

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

Alirocumab; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead
• Regeneron Pharmaceuticals: collaborator

Study Sites (9)

University Hospital Vienna (AKH)

Vienna, 1090, Austria

Location

Rigshospitalet

Copenhagen, 2100, Denmark

Location

Radboud Univerity, Nijmegen Medical Centre

Nijmegen, Gelderland, 6525, Netherlands

Location

Erasmus Thoraxcentre

Rotterdam, 3015, Netherlands

Location

Basel University Hospital

Basel, 4031, Switzerland

Location

Bern University Hospital Inselspital

Bern, 3010, Switzerland

Location

Hopitaux Universitaires Geneve

Geneva, 1211, Switzerland

Location

Stadtspital Triemli

Zurich, 8063, Switzerland

Location

University Hospital Zurich USZ

Zurich, 8091, Switzerland

Location

Related Publications (21)

• 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.

  PMID: 30336824 BACKGROUND

• 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.

  PMID: 27846344 BACKGROUND

• 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 Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2889-934. doi: 10.1016/j.jacc.2013.11.002. Epub 2013 Nov 12. No abstract available.

  PMID: 24239923 RESULT

• 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 tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015 May 14;36(19):1186-94. doi: 10.1093/eurheartj/ehv028. Epub 2015 Feb 16.

  PMID: 25687353 RESULT

• 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 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov 14;36(43):2996-3003. doi: 10.1093/eurheartj/ehv370. Epub 2015 Sep 1.

  PMID: 26330422 RESULT

• 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 reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1489-99. doi: 10.1056/NEJMoa1501031. Epub 2015 Mar 15.

  PMID: 25773378 RESULT

• Koskinas KC, Ughi GJ, Windecker S, Tearney GJ, Raber 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.

  PMID: 26655874 RESULT

• Raber L, Taniwaki M, Zaugg S, Kelbaek H, Roffi M, Holmvang L, Noble S, Pedrazzini G, Moschovitis A, Luscher TF, Matter CM, Serruys PW, Juni P, Garcia-Garcia HM, Windecker S; IBIS 4 (Integrated Biomarkers and Imaging Study-4) Trial Investigators (NCT00962416). Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular ultrasonography study. Eur Heart J. 2015 Feb 21;36(8):490-500. doi: 10.1093/eurheartj/ehu373. Epub 2014 Sep 2.

  PMID: 25182248 RESULT

• 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-infrared spectroscopy. Eur Heart J. 2012 Feb;33(3):372-83. doi: 10.1093/eurheartj/ehr387. Epub 2011 Oct 20.

  PMID: 22019821 RESULT

• 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 Cardiovasc Imaging. 2012 Mar;5(3 Suppl):S1-9. doi: 10.1016/j.jcmg.2011.11.019.

  PMID: 22421222 RESULT

• 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 large lipid core plaques at culprit sites in patients with acute ST-segment elevation myocardial infarction. JACC Cardiovasc Interv. 2013 Aug;6(8):838-46. doi: 10.1016/j.jcin.2013.04.012. Epub 2013 Jul 17.

  PMID: 23871513 RESULT

• Raber L, Zanchin T, Baumgartner S, Taniwaki M, Kalesan B, Moschovitis A, Garcia-Garcia HM, Justiz J, Pilgrim T, Wenaweser P, Meier B, Juni P, Windecker S. Differential healing response attributed to culprit lesions of patients with acute coronary syndromes and stable coronary artery after implantation of drug-eluting stents: an optical coherence tomography study. Int J Cardiol. 2014 May 1;173(2):259-67. doi: 10.1016/j.ijcard.2014.02.036. Epub 2014 Feb 28.

  PMID: 24631113 RESULT

• 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, Holm NR, Honda Y, Ikeno F, Kawasaki M, Kochman J, Koltowski L, Kubo T, Kume T, Kyono H, Lam CC, Lamouche G, Lee DP, Leon MB, Maehara A, Manfrini O, Mintz GS, Mizuno K, Morel MA, Nadkarni S, Okura H, Otake H, Pietrasik A, Prati F, Raber L, Radu MD, Rieber J, Riga M, Rollins A, Rosenberg M, Sirbu V, Serruys PW, Shimada K, Shinke T, Shite J, Siegel E, Sonoda S, Suter M, Takarada S, Tanaka A, Terashima M, Thim T, Uemura S, Ughi GJ, van Beusekom HM, van der Steen AF, van Es GA, van Soest G, Virmani R, Waxman S, Weissman NJ, Weisz G; International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT). Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. J Am Coll Cardiol. 2012 Mar 20;59(12):1058-72. doi: 10.1016/j.jacc.2011.09.079. Erratum In: J Am Coll Cardiol. 2012 May 1;59(18):1662. Dudeck, Darius [corrected to Dudek, Darius]; Falk, Erlin [corrected to Falk, Erling]; Garcia, Hector [corrected to Garcia-Garcia, Hector M]; Sonada, Shinjo [corrected to Sonoda, Shinjo]; Troels, Thim [corrected to Thim, Troels]; van Es, Gerrit-Ann [correct.

  PMID: 22421299 RESULT

• van der Velpen V, Haner JD, Kakizaki R, Bar S, Ueki Y, Siontis GCM, Stortecky S, Biccire FG, Ambuhl M, Kaiser C, Iglesias JF, Mach F, van Geuns RJ, Daemen J, Engstrom T, Ondracek AS, Lang I, Bourantas CV, Matter CM, Windecker S, Koskinas KC, Mayr M, Losdat S, Raber L, Haschke M, Spirk D. Intake of high-intensity statin after acute myocardial infarction assessed by direct drug concentration measurement: association with LDL-C response and coronary plaque modifications in the PACMAN-AMI trial. Eur J Prev Cardiol. 2025 Aug 12:zwaf457. doi: 10.1093/eurjpc/zwaf457. Online ahead of print.

  PMID: 40796144 DERIVED

• Koskinas KC, Haner J, Ueki Y, Otsuka T, Lonborg J, Shibutani H, Kakizaki R, Kaiser C, van Geuns RJ, Ondracek AS, Praz F, Ambuhl M, Spirk D, Lanz J, Daemen J, Heg D, Mayr M, Mach F, Windecker S, Engstrom T, Lang IM, von Eckardstein A, Losdat S, Raber L. Association of Lipoprotein(a) With Changes in Coronary Atherosclerosis in Patients Treated With Alirocumab. Circ Cardiovasc Imaging. 2024 Nov;17(11):e016683. doi: 10.1161/CIRCIMAGING.124.016683. Epub 2024 Nov 19.

  PMID: 39561225 DERIVED

• Biccire FG, Kakizaki R, Koskinas KC, Ueki Y, Haner J, Shibutani H, Lonborg J, Spitzer E, Iglesias JF, Otsuka T, Siontis GCM, Stortecky S, Kaiser C, Ambuhl M, Morf L, Ondracek AS, van Geuns RJ, Spirk D, Daemen J, Mach F, Windecker S, Engstrom T, Lang I, Losdat S, Raber L. Lesion-Level Effects of LDL-C-Lowering Therapy in Patients With Acute Myocardial Infarction: A Post Hoc Analysis of the PACMAN-AMI Trial. JAMA Cardiol. 2024 Dec 1;9(12):1082-1092. doi: 10.1001/jamacardio.2024.3200.

  PMID: 39221516 DERIVED

• Rexhaj E, Bar S, Soria R, Ueki Y, Haner JD, Otsuka T, Kavaliauskaite R, Siontis GC, Stortecky S, Shibutani H, Spirk D, Engstrom T, Lang I, Morf L, Ambuhl M, Windecker S, Losdat S, Koskinas KC, Raber L; PACMAN-AMI Investigators. Effects of alirocumab on endothelial function and coronary atherosclerosis in myocardial infarction: A PACMAN-AMI randomized clinical trial substudy. Atherosclerosis. 2024 May;392:117504. doi: 10.1016/j.atherosclerosis.2024.117504. Epub 2024 Mar 6.

  PMID: 38513436 DERIVED

• Biccire FG, Haner J, Losdat S, Ueki Y, Shibutani H, Otsuka T, Kakizaki R, Hofbauer TM, van Geuns RJ, Stortecky S, Siontis GCM, Bar S, Lonborg J, Heg D, Kaiser C, Spirk D, Daemen J, Iglesias JF, Windecker S, Engstrom T, Lang I, Koskinas KC, Raber L. Concomitant Coronary Atheroma Regression and Stabilization in Response to Lipid-Lowering Therapy. J Am Coll Cardiol. 2023 Oct 31;82(18):1737-1747. doi: 10.1016/j.jacc.2023.08.019. Epub 2023 Aug 26.

  PMID: 37640248 DERIVED

• Bar S, Kavaliauskaite R, Otsuka T, Ueki Y, Haner JD, Siontis GCM, Stortecky S, Shibutani H, Temperli F, Kaiser C, Iglesias JF, Jan van Geuns R, Daemen J, Spirk D, Engstrom T, Lang I, Windecker S, Koskinas KC, Losdat S, Raber L. Impact of alirocumab on plaque regression and haemodynamics of non-culprit arteries in patients with acute myocardial infarction: a prespecified substudy of the PACMAN-AMI trial. EuroIntervention. 2023 Jul 17;19(4):e286-e296. doi: 10.4244/EIJ-D-23-00201.

  PMID: 37341586 DERIVED

• Raber L, Ueki Y, Otsuka T, Losdat S, Haner JD, Lonborg J, Fahrni G, Iglesias JF, van Geuns RJ, Ondracek AS, Radu Juul Jensen MD, Zanchin C, Stortecky S, Spirk D, Siontis GCM, Saleh L, Matter CM, Daemen J, Mach F, Heg D, Windecker S, Engstrom T, Lang IM, Koskinas KC; PACMAN-AMI collaborators. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA. 2022 May 10;327(18):1771-1781. doi: 10.1001/jama.2022.5218.

  PMID: 35368058 DERIVED

• Zanchin C, Koskinas KC, Ueki Y, Losdat S, Haner JD, Bar S, Otsuka T, Inderkum A, Jensen MRJ, Lonborg J, Fahrni G, Ondracek AS, Daemen J, van Geuns RJ, Iglesias JF, Matter CM, Spirk D, Juni P, Mach F, Heg D, Engstrom T, Lang I, Windecker S, Raber L. 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-Rationale and design of the PACMAN-AMI trial. Am Heart J. 2021 Aug;238:33-44. doi: 10.1016/j.ahj.2021.04.006. Epub 2021 May 2.

  PMID: 33951415 DERIVED

MeSH Terms

Conditions

Plaque, Atherosclerotic

Interventions

alirocumab

Condition Hierarchy (Ancestors)

Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Study Officials

• Lorenz Raeber, Prof., MD

  Bern Universitiy Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2017
• First Posted: March 1, 2017
• Study Start: April 25, 2017
• Primary Completion: October 13, 2021
• Study Completion: October 13, 2021
• Last Updated: February 24, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); DK (1); NL (2); CH (5)