Functional Improvement of Coronary Artery Narrowing by Cholesterol Reduction With a PCSK9 Antibody (FITTER)

Functional Improvement of Non-infarcT relaTed Coronary Artery Stenosis by Extensive LDL-C Reduction With a PCSK9 Antibody

In a large number of patients who had a heart attack, multiple narrowings of the coronary arteries are identified. It is common practice to treat the narrowing that is the cause of the heart attack with a stent. It is not yet clearly known if the other narrowings in the other coronary arteries have to be treated immediately with a stent as well.

"Bad" cholesterol (LDL-cholesterol) can speed up the formation of these coronary artery narrowings, and can thus make the risk of a second heart attack bigger.

The investigators want to investigate if treating patients with the new cholesterol-lowering drug Evolocumab on top of the normal cholesterol lowering therapy (statins) ameliorates blood flow through coronary artery narrowings. Better blood flow through these narrowings could prevent the need for stenting or surgery in the future.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease; Atherosclerosis of Coronary Artery
• Intervention / Treatment: Drug: Evolocumab 140 MG/ML [Repatha]

Detailed Description

Rationale:

In a large number of patients presenting with acute coronary syndrome (ACS) multivessel disease (MVD) is identified. Optimal treatment approach for bystander lesions in non-infarct related arteries (non-IRA's) has not been well established. Multiple RCT's favor preventive percutaneous intervention (PCI) over medical treatment, however medical treatment wasn't optimal in these studies. Revascularization of lesions in the non-IRA can be guided by fractional flow reserve (FFR). The investigators want to investigate if optimizing LDL-C lowering therapy after an ACS has an effect on functional impairment of a non-IRA lesion and could thus prevent mechanical intervention (PCI or CABG).

Objective:

To evaluate the effect of maximal LDL-C reduction by Evolocumab on top of optimal background lipid-lowering therapy (ESC guidelines) on FFR of non-IRA lesions, in patients presenting with MVD-ACS.

Secondly to correlate baseline lipid core burden with changes in FFR and to investigate the relation between LDL-C reduction and change in pro-inflammatory monocyte phenotypes.

Study design: This is a multi-center, randomized, double blind, placebo controlled clinical trial.

Study population:

Patients presenting with MVD-ACS and eligible LDL-C levels will be included in this study. Patients must be 18 years or older. The investigators aim to include at least 150 patients to achieve adequate power for this study.

Intervention: The patients will be randomized 1:1 to (A), one group will receive 140mg Evolocumab every two weeks (Q2W) for 12 weeks, using personal injectors; (B) the other group will receive placebo. All participants will receive high intensity statin therapy (HIST) as background therapy (Atorvastatin 40mg or equivalent).

Main study parameters/endpoints:

The primary study parameter is the change in FFR from baseline to follow-up in non-IRA lesions. The secondary invasive imaging endpoint is the correlation between baseline Near-InfraRed Spectroscopy (NIRS) derived lipid core burden (MaxLCBI4mm) and change in FFR of the non-IRA.

The investigators will assess the index of microcirculatory resistance (IMR) as an exploratory endpoint.

Main endpoint for the immunological parameters is the comparison of monocyte phenotype between the groups at t=12 weeks post-ACS.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

After inclusion, all patients have to undergo staged FFR + NIRS, meaning they will undergo invasive strategy for a second time, and if needed additional stenting of significant lesions, with the associated periprocedural risks (e.g. death, stroke, myocardial infarction (MI), vascular complications), however these risks are quite small (<2% major complications) .

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Frans B Mensink, MD, MSc; Phone Number: +31 (0) 24 3092476; Email: frans.mensink@radboudumc.nl
• Study Contact Backup: Name: Robert Jan van Geuns, MD, PhD; Phone Number: +31 (0) 24 3614533; Email: robertjan.vangeuns@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Recruiting
      • Radboud University Medical Center
      • Contact: Frans Mensink, Msc.; Phone Number: +31(0)243092476; Email: frans.mensink@radboudumc.nl

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria (all):

• ACS with PCI of infarct related artery
• MVD
• FFR of non-IRA lesion 0.67 - 0.80
• Subjects must have an eligible LDL-C level via local lab assessment based on statin use at screening:
• No statin use: 130 mg/dL (3.3 mmol/l)
• Non-intensive statin use: 80 mg/dL (2.0 mmol/l)
• Intensive statin use 60mg/dL (1.6 mmol/l)
• 18 years old at screening

Exclusion Criteria (any):

• Refusal or inability to provide informed consent
• Prior coronary artery bypass graft
• Known left ventricular ejection fraction (LVEF)<30%
• Untreated functional left main stem stenosis (FFR<0.81)
• Contra-indication for dual antiplatelet therapy
• Chronic total occlusion of a non-IRA
• Non-IRA stenosis not amenable for PCI treatment (operators decision)
• Complicated infarct related artery (IRA) treatment, with one or more of the following:
• Extravasation
• Permanent no re-flow after IRA treatment (TIMI flow 0-1)
• Inability to implant a stent
• Known severe cardiac valve dysfunction that will require surgery in the follow-up period.
• Severe kidney disease defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min.
• Female subject is pregnant, breastfeeding or planning to become pregnant or planning to breastfeed during treatment and for an additional 15 weeks after the last dose of investigational product. Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive serum pregnancy test.
• Female subjects of childbearing potential unwilling to use 1 acceptable method of effective contraception during treatment and for an additional 15 weeks after the last dose of investigational product.
• Female subject who has not used an acceptable method(s) of birth control for at least 1 month prior to screening, unless the female subject is sterilized or postmenopausal.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment arm; Evolocumab (140mg) will be administered subcutaneously every two weeks (Q2W) on day 1 through week 12 with personal injectors, containing 1 mL deliverable volume of 140 mg/mL Evolocumab.	Drug: Evolocumab 140 MG/ML [Repatha]; Evolocumab (also known as Repatha, formerly referred to as AMG 145) is a human monoclonal immunoglobulin G2 (IgG2) that specifically binds to proprotein convertase subtilisin/kexin type 9 (PCSK9) preventing its interaction with the low-density lipoprotein receptor (LDLR). The inhibition of PCSK9 by evolocumab leads to increased LDLR expression and subsequent decreased circulating concentrations of low-density lipoprotein cholesterol (LDL-C).; Other Names: Repatha; AMG145
Placebo Comparator: Comparator arm; Placebo will be administered subcutaneously every two weeks (Q2W) on day 1 through week 12 with personal injectors, containing 1 mL deliverable volume of placebo.	Drug: Evolocumab 140 MG/ML [Repatha]; Evolocumab (also known as Repatha, formerly referred to as AMG 145) is a human monoclonal immunoglobulin G2 (IgG2) that specifically binds to proprotein convertase subtilisin/kexin type 9 (PCSK9) preventing its interaction with the low-density lipoprotein receptor (LDLR). The inhibition of PCSK9 by evolocumab leads to increased LDLR expression and subsequent decreased circulating concentrations of low-density lipoprotein cholesterol (LDL-C).; Other Names: Repatha; AMG145

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in FFR from baseline to follow-up in non-IRA lesions.	Fractional flow reserve (FFR): FFR is the ratio between coronary pressure distal from a stenotic lesion and aortic pressure proximal to that lesion during maximal hyperaemia. Flow is linearly related to blood pressure when coronary resistance is minimal. Thus FFR is a surrogate measure for the proportion of flow across a stenosis.	FFR will be assessed at baseline (0 weeks) and at the last follow-up visit (12 weeks).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The correlation between baseline Near-InfraRed Spectroscopy (NIRS) derived lipid core burden (MaxLCBI4mm) and change in FFR of the non-IRA.	NIRS is an imaging method used to detect lipid-rich plaques in a coronary artery. The fraction of yellow pixels obtained from the chemogram, an image map derived from the NIRS measurements, is multiplied by 1000 to compute the Lipid Core Burden Index (LCBI).	NIRS will be performed at baseline (0 weeks) and at last follow-up visit (12 weeks).
The correlation between LDL-C reduction and reduction of pro-inflammatory monocyte phenotypes.	Monocyte phenotype will be determined using a Flow Cytometry Panel Design (FACS) panel and cytokine production capacity of peripheral blood mononuclear cells after 24h incubation with lipopolysaccharide/Pam3Cys(LPS/Pam3Cys) and cholesterol crystals (IL-1b). At baseline (0 weeks), 4 and 12 weeks measurements will be repeated (in the morning after overnight fast) with additional magnetic activated cell separation (MACS) isolation of monocytes for RNA and chromatin immunoprecipitation (ChiP)-sequencing.	Blood for monocyte phenotyping will be drawn directly after revascularization at baseline (0 weeks). Measurements will be repeated at 4 weeks and 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Index of Microcirculatory Resistance (IMR).	The apparent IMR is calculated by multiplying the distal coronary pressure by the mean transit time of a 3 ml bolus of saline at room temperature during coronary hyperemia induced by intravenous adenosine. This will be an exploratory endpoint.	This measurement will be performed at baseline (0 weeks) and at last follow-up visit (12 weeks)
Percentage of lesions with a FFR >0.80 at follow-up.	The percentage of lesions with a FFR >0.80 at follow-up will be listed and tabulated.	This endpoint is measured at the last study visit (12 weeks).
Patient-oriented composite endpoint (POCE): composite of all-cause death, any stroke, any MI and any revascularization, unplanned ischemia driven PCI of the target lesion, any unplanned ischemia driven PCI in the total study population.	Event rates of POCE will be listed and tabulated.	This endpoint is measured during the study, and terminates at the last study visit (12 weeks).

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Amgen
• Investigators: Principal Investigator: Robert Jan van Geuns, MD, PhD, robertjan.vangeuns@radboudumc.nl

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2020
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): June 1, 2023

Study Registration Dates

• First Submitted: October 22, 2019
• First Submitted That Met QC Criteria: October 24, 2019
• First Posted (Actual): October 28, 2019

Study Record Updates

• Last Update Posted (Actual): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: NL71538.091.19

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No