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

NCT03287609 | Completed Phase 3 DMC

• 1 other identifier: 2017-01753
• Study Type: interventional
• Target: 308
• Locations: 1 country
• Sites: 7

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

Outcome Measures

Primary Outcomes (1)

• Percent change in calculated LDL-C in the intent to treat (ITT) population

  Baseline to week 8

Secondary Outcomes (1)

• Number of patients with adverse events and serious adverse events

  Baseline to week 8

Other Outcomes (18)

• Nominal change in calculated LDL-C

  Baseline to week 8

• Proportion of patients with LDL-C level <70 mg/dL (<1.8 mmol/L) at week 8

  Baseline to week 8

• Change in total cholesterol in the ITT population

  Baseline to week 8

Study Arms (2)

Evolocumab

ACTIVE COMPARATOR

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

Drug: Evolocumab 140 mg/mL

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Evolocumab 140 mg/mL DRUG

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

Evolocumab

Placebo DRUG

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

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 ≥ 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead
• Amgen: collaborator
• University of Bern: collaborator

Study Sites (7)

Basel University Hospital

Basel, Canton of Basel-City, 4031, Switzerland

Location

HFR Kantonsspital

Fribourg, Canton of Fribourg, 1708, Switzerland

Location

Hopitaux Universitaires Geneve

Geneva, Canton of Geneva, 1211, Switzerland

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, Canton of Vaud, Switzerland

Location

University Hospital

Zurich, Canton of Zurich, Switzerland

Location

Cardiocentro Ticino

Lugano, Canton Ticino, 6900, Switzerland

Location

Bern University Hospital

Bern, 3010, Switzerland

Location

Related Publications (6)

• 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.

  PMID: 28304224 RESULT

• 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.

  PMID: 26578202 RESULT

• 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.

  PMID: 16226162 RESULT

• 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.

  PMID: 11277825 RESULT

• 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.

  PMID: 26999484 RESULT

• 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.

  PMID: 31479722 DERIVED

MeSH Terms

Conditions

Acute Coronary Syndrome

Interventions

evolocumab

Condition Hierarchy (Ancestors)

Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases

Study Officials

• Stephan Windecker, Prof., MD

  Bern University Hospital

  STUDY CHAIR

• Konstantinos Koskinas, MD

  Bern University 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: September 7, 2017
• First Posted: September 19, 2017
• Study Start: January 23, 2018
• Primary Completion: May 20, 2019
• Study Completion: August 7, 2019
• Last Updated: August 14, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will not share

Locations

CH (7)