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

• ClinicalTrials.gov Identifier: NCT03287609
• Recruitment Status: Completed
• First Posted: September 19, 2017
• Last Update Posted: August 14, 2019
• Sponsor: University Hospital Inselspital, Berne
• Collaborators: Amgen; University of Bern
• Information provided by (Responsible Party): University Hospital Inselspital, Berne

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Acute Coronary Syndrome	Drug: Evolocumab 140 mg/mL; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 308 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: EVOlocumab for Early Reduction of LDL-cholesterol Levels in Patients With Acute Coronary Syndromes (EVOPACS) - A Randomized, Double-blind, Placebo-controlled Multicenter Study
• Actual Study Start Date: January 23, 2018
• Actual Primary Completion Date: May 20, 2019
• Actual Study Completion Date: August 7, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Evolocumab; Evolocumab 140 mg/mL, pre-filled auto-injector pen, 3 injections at day 1 and week 4	Drug: Evolocumab 140 mg/mL; Three injections with pre-filled auto-injector pen at day 1 and at week 4.
Placebo Comparator: Placebo; Placebo, pre-filled auto-injector pen, 3 injections at day 1 and week 4	Drug: Placebo; Three injections with pre-filled auto-injector pen at day 1 and at week 4.

Outcome Measures

Primary Outcome Measures :

1. Percent change in calculated LDL-C in the intent to treat (ITT) population [ Time Frame: Baseline to week 8 ]

Secondary Outcome Measures :

1. Number of patients with adverse events and serious adverse events [ Time Frame: Baseline to week 8 ]

Other Outcome Measures:

1. Nominal change in calculated LDL-C [ Time Frame: Baseline to week 8 ]
2. Proportion of patients with LDL-C level <70 mg/dL (<1.8 mmol/L) at week 8 [ Time Frame: Baseline to week 8 ]
3. Change in total cholesterol in the ITT population [ Time Frame: Baseline to week 8 ]
4. Change in HDL-C in the ITT population [ Time Frame: Baseline to week 8 ]
5. Change in lipoprotein-a in the ITT population [ Time Frame: Baseline to week 8 ]
6. Change in triglycerides in the ITT population [ Time Frame: Baseline to week 8 ]
7. Change in non-HDL-C in the ITT population [ Time Frame: Baseline to week 8 ]
8. Change in apolipoprotein B in the ITT population [ Time Frame: Baseline to week 8 ]
9. Change in apolipoprotein A-1 in the ITT population [ Time Frame: Baseline to week 8 ]
10. Percent change in high-sensitivity CRP (hs-CRP) in the ITT population [ Time Frame: Baseline to week 8 ]
11. Proportion of patients with hs-CRP level <2 mg/dL at week 8 in the ITT population [ Time Frame: Baseline to week 8 ]
12. Proportion of patients with LDL-C <70 mg/dL and hs-CRP <2 mg/dL at week 8 in the ITT population [ Time Frame: Baseline to week 8 ]
13. Nominal change in Interleukin (IL)-1b and IL-6 in the ITT population [ Time Frame: Baseline to week 8 ]
14. Change in high-sensitivity Troponin T [ Time Frame: Baseline to 72 hours ]
15. Area under the curve (AUC) at Multiplate with Adenosinediphosphate (ADP) test [ Time Frame: Baseline to 72 hours and to week 8 ]
    Platelet inhibition assessed with Multiplate ADP test at 72 hours and 8 weeks
16. Area under the curve (AUC) at Multiplate with Thrombin receptor activating peptide (TRAP) test [ Time Frame: Baseline to 72 hours and to week 8 ]
    Platelet inhibition assessed with Multiplate TRAP test at 72 hours and 8 weeks
17. Number of patients with contrast-induced acute kidney injury (CI-AKI) at 72 hours among patients who undergo coronary angiography at baseline [ Time Frame: Baseline to 72 hours ]
18. Number of patients with adjudicated events (death, cardiovascular death, myocardial infarction, hospitalization for recurrent ACS, hospitalization for heart failure, coronary revascularization, stroke [ Time Frame: Baseline to week 8 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Switzerland

Basel University Hospital

Basel, BS, Switzerland, 4031

HFR Kantonsspital

Fribourg, FR, Switzerland, 1708

Hopitaux Universitaires Geneve

Geneva, GE, Switzerland, 1211

Cardiocentro Ticino

Lugano, TI, Switzerland, 6900

Centre Hospitalier Universitaire Vaudois

Lausanne, VD, Switzerland

University Hospital

Zurich, ZH, Switzerland

Bern University Hospital

Bern, Switzerland, 3010

Sponsors and Collaborators

University Hospital Inselspital, Berne

Amgen

University of Bern

Investigators

• Study Chair: Stephan Windecker, Prof., MD; Bern University Hospital
• Principal Investigator: Konstantinos Koskinas, MD; Bern University Hospital

More Information

Publications of Results:

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.

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.

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: University Hospital Inselspital, Berne
• ClinicalTrials.gov Identifier: NCT03287609
• Other Study ID Numbers: 2017-01753
• First Posted: September 19, 2017
• Last Update Posted: August 14, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: No plan to make individual participant data available to other researchers

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Acute Coronary Syndrome; Syndrome; Disease; Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Evolocumab; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents