Markers of Cardiovascular Risk in Patients With Premature Coronary Artery Disease and Treatment (GEBI)

October 27, 2020 updated by: Miran Sebestjen, University Medical Centre Ljubljana

Genetic, Biochemical and Functional Markers of Cardiovascular Risk in Patients With Premature Coronary Artery Disease and Treatment Options

The aim of study is to examine the relationship between lipid subfractions, inflammation and structural-functional properties of the arterial wall in patients with premature coronary heart disease, to study genetic polymorphisms that determine lipid subfractions concentration on the functional and morphological properties of the arterial vascular wall in patients with early coronary heart disease, to study the effect of alirocumab and evolocumab on lipid subfractions, inflammation and structural-functional properties of arterial wall in patients with early coronary atherosclerosis and to study the influence of NOS-3 gene expression on the functional and morphological properties of the arterial vascular wall in the same patients. Impaired blood fat metabolism and chronic inflammation are intertwined as possible causes of atherosclerosis. Lipoprotein (a) (Lp (a)) is an important risk factor for coronary heart disease and a prognostic predictor in patients after myocardial infarction, but recent research suggests that subtilisin-kexin convertase type 9 (PCSK9) inhibitors are the only drugs that significantly reduce serum Lp (a) concentration. However, there are no data on the relationship between Lp (a) values and polymorphisms for Lp (a), indicators of inflammation and impaired arterial function, and response to treatment with various PCSK9 inhibitors in patients with early coronary heart disease.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Impaired blood fat metabolism and chronic inflammation are intertwined as possible causes of atherosclerosis. Lipoprotein (a) (Lp (a)) is a specific subfraction of lipoprotein that is an independent risk factor for coronary heart disease and at the same time predicted residual risk in patients with pre-existing atherosclerosis, regardless of serum LDL-cholesterol concentration. Circulating levels of Lp(a) are mainly genetically determined and varies according to ethnic group. Lp(a) has many functions, which include atherosclerotic, prothrombotic and pro-inflammatory roles. The gene encoding apo (a); LPA, is located on the long arm of chromosome 6 (6q2,6-2,7) and most variants in Lp (a) can be explained by genetic diversity in LPA. To date, the most studied genetic variant is the Kringle-IV type-2 (KIV2) polymorphism, which explains 30-70% of the diversity in Lp (a) in the population. Some KIV2 replicates are associated with smaller isoforms and higher plasma concentrations of Lp (a) which are causally and independently associated with coronary heart disease. Within LPA, the number of KIV2 copies, as well as one nucleotide polymorphism (SNP), rs3798220 and rs10455872, is associated with Lp (a) concentration and coronary heart disease. Recently 'Proprotein convertase subtilisin/kexin type 9' (PCSK9) inhibitors that act through non-specific reduction of Lp(a) are the only drugs that have shown effectiveness in clinical trials, to provide reductions in cardiovascular morbidity and mortality. The effects of PCSK9 inhibitors are not purely through Lp(a) reduction, but also through LDL cholesterol reduction.

The early stage of the atherosclerosis process is characterized by endothelial cell damage, which results in impaired release and function of nitric oxide (NO) from the endothelium. NO is formed by endothelial NO synthetase (NOS-3) from the amino acid L-arginine, which is most pronounced in the vascular wall and is also most important in the process of atherosclerosis. The NOS-3 gene is located on chromosome 7; in the region 7q35-7q36. Functional polymorphisms are those that alter the expression or activity of NOS-3. Among them, rs2070744, rs3918226 and rs1799983 single nucleotide polymorphisms (SNP) are important. Variations in the expression and activity of NOS-3 genetic polymorphisms at exon 7 of the NOS-3 gene are associated with the incidence of myocardial infarction in very young patients who otherwise have a low atheromatous coronary artery load. Variations in the NOS-3 genes cause diversity in NO bioavailability and are responsible for endothelial dysfunction.

A 6-month observational, prospective, and randomized study will include 70 patients with a first acute coronary syndrome (ACS) (including acute transmural myocardial infarction, nontransmural myocardial infarction or unstable angina pectoris) event before age 55 and Lp (a) levels above 1000 mg / L or Lp (a) above 600 mg / L and LDL above 2.6 mmol / L. With the gradual inclusion ("step-wedge") and randomization of patients, the investigators will also provide a control group that will include 30 patients. The investigators will do anamnesis, targeted clinical examination, take blood samples for laboratory measurements, ultrasound measure endothelium-dependent dilatation of the brachial artery and intima media thickness of carotid arteries, measure pulse wave and calculate carotid artery wall stiffness. Patients will be divided into three groups according to a randomization list. The first group will receive alirocumab, the second group evolocumab, and the third group will be the control group and will be included in the treatment after 6 months. During this time, the control group will not receive treatment with alirocumab or evolocumab, only standard treatment. After 6 months, the investigators will repeat all the mentioned investigations. Patients will be informed about the purpose and course of the study before starting it. All will participate voluntarily, without pressure or inappropriate instigation, which they will confirm by signing.

The investigators hypotheses that in patients with early coronary artery disease Lp (a) and Lp (a) polymorphisms are associated with indicators of inflammation and structural-functional properties of the arterial wall; in patients with early coronary artery disease, PCSK9 inhibitors reduce the value of Lp (a), indicators of inflammation and structural and functional involvement of the arterial wall; in patients with early coronary artery disease, the influence of PCSK9 inhibitors on Lp (a), indicators of inflammation and structural-functional properties of the arterial wall depends on the presence of specific polymorphisms for Lp (a).

Study Type

Interventional

Enrollment (Anticipated)

70

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Slovenia
      • Ljubljana, Slovenia, 1000
        • Recruiting
        • University Medical Centre Ljubljana-Department of Vascular diseases and dept. of Cardiology
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • at least 6 months after acute coronary syndrome,
  • up to 55 years at the time of first acute coronary syndrome
  • concentration Lp (a) above 1000 mg / L or Lp (a) above 600 mg / L and LDL above 2.6 mmol / L
  • optimally treated risk factors for cardiovascular events according to currently valid guidelines.

Exclusion Criteria:

  • Age <18 years or > 65 years,
  • documented history of myocardial infarction less than 6 months before enrollment
  • secondary dyslipidemia,
  • severe renal disease (oGFR <30 ml / min),
  • moderate to severe liver disease (elevated transaminases above 3 times the norm, elevated bilirubin above 2 times the norm, elevated creatinine kinase above 3 times the norm),
  • acute illness 6 weeks before inclusion in the study,
  • history of allergic reaction to any ingredient in the drug,
  • pregnancy and lactation,
  • life expectancy less than 12 months,
  • unwillingness to participate or lack of availability for follow-up

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Alirocumab
The first group of patients will receive 150 mg of alirocumab every two weeks subcutaneously for 6 months
Drug: Alirocumab
The first group will receive alirocumab. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
Experimental: Evolocumab
the second group of patients will receive evolocumab 140 mg every two weeks subcutaneously for 6 months
Drug: Evolocumab
The second group will receive evolocumab. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.
Experimental: Control group
Control group will be included in the treatment after 6 months. During this time, the control group will not receive treatment with alirocumab or evolocumab, only standard guidelines-based treatment
Drug: Control group
The third group will receive only optimal guidelines-based secondary preventive treatment. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery, intima media thickness of carotid arteries and pulse wave will be measured.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ultrasound functional and morphological properties of the arterial wall and Lp (a) concentration
Time Frame: Baseline
Functional and morphological characteristics of arterial wall will correlate to Lp (a) concentrations.
Baseline
Concentration of Lp (a) and SNP in the LPA gene
Time Frame: Baseline
The serum concentration of Lp (a) will correlate with single nucleotide polymorphisms (SNP) in the LPA gene
Baseline
The effect of alirocumab or evolocumab on functional and morphological properties of arterial wall after 6 months
Time Frame: 6 months
Both drugs will improve functional and morphological properties of arterial wall in with no difference between the drugs. We expect the improvements in each drug group will be in correlation with the decrease of Lp (a) concentration.
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Medical Centre Ljubljana

Investigators

  • Study Chair: Miran Šebeštjen, prof., University Medical Centre Ljubljana (Slovenia)
  • Principal Investigator: Andreja Rehberger Likozar, MD, University Medical Centre Ljubljana (Slovenia)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

November 10, 2020

Primary Completion (Anticipated)

June 30, 2021

Study Completion (Anticipated)

October 1, 2021

Study Registration Dates

First Submitted

October 6, 2020

First Submitted That Met QC Criteria

October 27, 2020

First Posted (Actual)

November 3, 2020

Study Record Updates

Last Update Posted (Actual)

November 3, 2020

Last Update Submitted That Met QC Criteria

October 27, 2020

Last Verified

October 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GEBI

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Inflammation

Clinical Trials on Alirocumab

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Bahamas

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe