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

Acute Coronary Syndrome Clinical Trial

— EVOPACS  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03287609
• Other study ID #: 2017-01753
• Status: Completed
• Phase: Phase 3
• Start date: January 23, 2018
• Est. completion date: August 7, 2019

Study information

• Verified date: August 2019
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 308
• Est. completion date: August 7, 2019
• Est. primary completion date: May 20, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Syndrome

Intervention

Drug:
• Evolocumab 140 mg/mL
Three injections with pre-filled auto-injector pen at day 1 and at week 4.
• Placebo
Three injections with pre-filled auto-injector pen at day 1 and at week 4.

Locations

Country	Name	City	State
Switzerland	Basel University Hospital	Basel	BS
Switzerland	Bern University Hospital	Bern
Switzerland	HFR Kantonsspital	Fribourg	FR
Switzerland	Hopitaux Universitaires Geneve	Geneva	GE
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne	VD
Switzerland	Cardiocentro Ticino	Lugano	TI
Switzerland	University Hospital	Zurich	ZH

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne	Amgen, University of Bern

Country where clinical trial is conducted

Switzerland, 

References & Publications (5)

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 prim — View Citation

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/M15-29 — View Citation

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 — View Citation

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. — View Citation

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 ischem — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Nominal change in calculated LDL-C		Baseline to week 8
Other	Proportion of patients with LDL-C level <70 mg/dL (<1.8 mmol/L) at week 8		Baseline to week 8
Other	Change in total cholesterol in the ITT population		Baseline to week 8
Other	Change in HDL-C in the ITT population		Baseline to week 8
Other	Change in lipoprotein-a in the ITT population		Baseline to week 8
Other	Change in triglycerides in the ITT population		Baseline to week 8
Other	Change in non-HDL-C in the ITT population		Baseline to week 8
Other	Change in apolipoprotein B in the ITT population		Baseline to week 8
Other	Change in apolipoprotein A-1 in the ITT population		Baseline to week 8
Other	Percent change in high-sensitivity CRP (hs-CRP) in the ITT population		Baseline to week 8
Other	Proportion of patients with hs-CRP level <2 mg/dL at week 8 in the ITT population		Baseline to week 8
Other	Proportion of patients with LDL-C <70 mg/dL and hs-CRP <2 mg/dL at week 8 in the ITT population		Baseline to week 8
Other	Nominal change in Interleukin (IL)-1b and IL-6 in the ITT population		Baseline to week 8
Other	Change in high-sensitivity Troponin T		Baseline to 72 hours
Other	Area under the curve (AUC) at Multiplate with Adenosinediphosphate (ADP) test	Platelet inhibition assessed with Multiplate ADP test at 72 hours and 8 weeks	Baseline to 72 hours and to week 8
Other	Area under the curve (AUC) at Multiplate with Thrombin receptor activating peptide (TRAP) test	Platelet inhibition assessed with Multiplate TRAP test at 72 hours and 8 weeks	Baseline to 72 hours and to week 8
Other	Number of patients with contrast-induced acute kidney injury (CI-AKI) at 72 hours among patients who undergo coronary angiography at baseline		Baseline to 72 hours
Other	Number of patients with adjudicated events (death, cardiovascular death, myocardial infarction, hospitalization for recurrent ACS, hospitalization for heart failure, coronary revascularization, stroke		Baseline to week 8
Primary	Percent change in calculated LDL-C in the intent to treat (ITT) population		Baseline to week 8
Secondary	Number of patients with adverse events and serious adverse events		Baseline to week 8