EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS)

NCT ID: NCT03287609

Last Updated: 2019-08-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 308 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-23
• Study Completion Date: 2019-08-07

Brief Summary

Reduction of low-density lipoprotein cholesterol (LDL-C) levels effectively reduces the risk of adverse events in patients with established atherosclerotic cardiovascular disease. The clinical benefit of statins in improving clinical outcomes is proportional to the magnitude of LDL-C reduction, is more pronounced in patients with acute coronary syndromes (ACS) compared with stable coronary artery disease, and emerges at very early stages (as early as 4 weeks) after ACS when statins are administered in the acute phase of the event. On the basis of this evidence, early initiation of statin therapy is currently recommended in patients presenting with ACS. Because many patients cannot achieve adequate reduction of LDL-C levels despite treatment with high doses of statins or non-statin lipid-modifying medications, substantial residual risk remains. Moreover, the time of onset of LDL-C reduction takes 2 weeks following initiation of statin therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors represent a novel class of lipid-lowering drugs leading to rapid, profound, and consistent reductions in LDL-C levels. While the effectiveness of PCSK9 monoclonal antibodies for LDL-C lowering has been established across patient populations without atherosclerotic cardiovascular disease or with stable ischemic heart disease, reduction and attainment of LDL-C target levels has not been explored in the acute setting of ACS - a clinical setting with highest risk of early event recurrence (within the first month). In this study the investigators want to evaluate the safety and effectiveness of the PCSK9 inhibitor evolocumab as compared with placebo, administered in the acute phase of ACS, for reduction of LDL-C levels within 8 weeks in patients receiving guideline-recommended high-intensity statin treatment (atorvastatin 40mg QD).

Conditions

Acute Coronary Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Evolocumab

Evolocumab 140 mg/mL, pre-filled auto-injector pen, 3 injections at day 1 and week 4

Group Type: ACTIVE_COMPARATOR

Evolocumab 140 mg/mL

Intervention Type: DRUG

Three injections with pre-filled auto-injector pen at day 1 and at week 4.

Placebo

Placebo, pre-filled auto-injector pen, 3 injections at day 1 and week 4

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Three injections with pre-filled auto-injector pen at day 1 and at week 4.

Interventions

Evolocumab 140 mg/mL

Three injections with pre-filled auto-injector pen at day 1 and at week 4.

Intervention Type: DRUG

Placebo

Three injections with pre-filled auto-injector pen at day 1 and at week 4.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Male or female ≥ 18 years of age;

• Hospitalized for a recent ACS;
• LDL-C levels defined as follows:
• LDL-C ≥70 mg/dL (≥1.8 mmol/L) or non-HDL-C ≥100 mg/dL (≥2.6 mmol/) in patients who have been receiving stable treatment with high-intensity statin within ≥ 4 weeks prior to enrollment (i.e. continuous treatment that has not changed with regard to statin intensity over the past 4 weeks) or, LDL-C ≥90 mg/dL (≥2.3 mmol/L) or non-HDL-C ≥120 mg/dL (≥3.1 mmol/) in patients who have been receiving stable treatment with low- or moderate-intensity statin within ≥ 4 weeks prior to enrollment (i.e. continuous treatment that has not changed with regard to statin intensity over the past 4 weeks), or LDL-C ≥125 mg/dL (≥3.2 mmol/L) or non-HDL-C ≥155 mg/dL (≥4.0 mmol/) in patients who are statin-naïve or have not been on a stable (unchanged) statin regimen for at least 4 weeks prior to enrollment;
• Ability to understand the requirements of the study and to provide informed consent.

Exclusion Criteria

• Unstable clinical status (hemodynamic or electrical instability;
• 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, either reported in patient medical record or defined by asparate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 3x the upper limit of normal;
• Reported intolerance to atorvastatin (any dose) OR statin intolerance;
• Known allergy to contrast medium, heparin, aspirin, ticagrelor or prasugrel;
• Known sensitivity to any substances to be administered;
• Patients who previously received evolocumab 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 systemic cyclosporine, systemic steroids (eg. intravenous, intramuscular or per os);
• Known active infection or major hematologic, metabolic, or endocrine dysfunction in the judgment of the Investigator;
• Patients who will not be available for study-required procedures in the judgment of the Investigator;
• Current enrollment in another investigational device or drug study;
• Active malignancy requiring treatment;
• Female of childbearing potential (age <50 years and last menstruation within the last 12 months), who did not undergo tubal ligation, ovariectomy or hysterectomy.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: collaborator

University of Bern

OTHER

Sponsor Role: collaborator

Insel Gruppe AG, University Hospital Bern

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephan Windecker, Prof., MD

Role: STUDY_CHAIR

Bern University Hospital

Konstantinos Koskinas, MD

Role: PRINCIPAL_INVESTIGATOR

Bern University Hospital

Locations

Basel University Hospital

Basel, Canton of Basel-City, Switzerland

HFR Kantonsspital

Fribourg, Canton of Fribourg, Switzerland

Hopitaux Universitaires Geneve

Geneva, Canton of Geneva, Switzerland

Centre Hospitalier Universitaire Vaudois

Lausanne, Canton of Vaud, Switzerland

University Hospital

Zurich, Canton of Zurich, Switzerland

Cardiocentro Ticino

Lugano, Canton Ticino, Switzerland

Bern University Hospital

Bern, , Switzerland

Countries

Switzerland

References

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.

Reference Type: RESULT

PMID: 28304224 (View on PubMed)

Lipinski MJ, Benedetto U, Escarcega RO, Biondi-Zoccai G, Lhermusier T, Baker NC, Torguson R, Brewer HB Jr, Waksman R. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J. 2016 Feb 7;37(6):536-45. doi: 10.1093/eurheartj/ehv563. Epub 2015 Nov 17.

Reference Type: RESULT

PMID: 26578202 (View on PubMed)

Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E; PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2005 Oct 18;46(8):1405-10. doi: 10.1016/j.jacc.2005.03.077.

Reference Type: RESULT

PMID: 16226162 (View on PubMed)

Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T; Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001 Apr 4;285(13):1711-8. doi: 10.1001/jama.285.13.1711.

Reference Type: RESULT

PMID: 11277825 (View on PubMed)

Navarese EP, Kolodziejczak M, Kereiakes DJ, Tantry US, O'Connor C, Gurbel PA. Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies for Acute Coronary Syndrome: A Narrative Review. Ann Intern Med. 2016 May 3;164(9):600-7. doi: 10.7326/M15-2994. Epub 2016 Mar 22.

Reference Type: RESULT

PMID: 26999484 (View on PubMed)

Koskinas KC, Windecker S, Pedrazzini G, Mueller C, Cook S, Matter CM, Muller O, Haner J, Gencer B, Crljenica C, Amini P, Deckarm O, Iglesias JF, Raber L, Heg D, Mach F. Evolocumab for Early Reduction of LDL Cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS). J Am Coll Cardiol. 2019 Nov 19;74(20):2452-2462. doi: 10.1016/j.jacc.2019.08.010. Epub 2019 Aug 31.

Reference Type: DERIVED

PMID: 31479722 (View on PubMed)

Other Identifiers

2017-01753

Identifier Type: -

Identifier Source: org_study_id