Influence of Pelacarsen on Patients After Myocardial Infarction With High Lp(a) Values (PEMILA)

December 10, 2021 updated by: Miran Sebestjen, University Medical Centre Ljubljana

Influence of Pelacarsen on Arterial Wall Properties and Risk Factors in Patients After Myocardial Infarction With High Lp(a) Values

The aim of study is to examine the relationship between lipid subfractions, inflammation and structural-functional properties of the arterial wall in patients after myocardial infarction with high lipoprotein (a) (Lp (a)) levels, to study genetic polymorphisms that determine lipid subfractions concentration on the functional and morphological properties of the arterial vascular wall in patients after myocardial infarction with high Lp (a) levels, to study the effect of pelacarsen on lipid subfractions, inflammation and structural-functional properties of arterial wall in patients after myocardial infarction with high Lp (a) levels 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 represent possible causes of atherosclerosis. Lp (a) is an independent risk factor for cardiovascular disease and a prognostic predictor in patients after myocardial infarction. Despite recommended screening for elevated Lp (a), there is no specific drug treatment approved to reduce cardiovascular risk through lowering Lp (a). Besides subtilisin-kexin convertase type 9 (PCSK9) inhibitors, antisense oligonucleotides (ASOs) are currently only therapeutic agents that significantly reduce serum Lp (a) concentration. Pelacarsen by using an ASO directed against the messenger ribonucleic acid (mRNA) of apolipoprotein (a), reduces the production of apolipoprotein (a) in the liver and thus, the level of Lp (a).

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 pelacarsen in patients after myocardial infarction with extremely high Lp (a) levels.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Impaired blood fat metabolism and chronic inflammation represent possible causes of atherosclerosis. 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 functional polymorphisms, rs2070744, rs3918226 and rs1799983 single nucleotide polymorphisms (SNP) are important. Variations in the NOS-3 genes cause diversity in NO bioavailability and are responsible for endothelial dysfunction.

Lipoprotein (a) (Lp (a)) is a specific subfraction of lipoprotein that is an independent risk factor for cardiovascular disease and predicts the 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 atherosclerotic, prothrombotic and pro-inflammatory effects. 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, are associated with Lp (a) concentration and coronary heart disease. Besides subtilisin-kexin convertase type 9 (PCSK9) inhibitors, antisense oligonucleotides (ASOs) are currently only therapeutic agents that significantly reduce serum Lp (a) concentration and that have shown effectiveness in clinical trials, to provide reductions in cardiovascular morbidity and mortality. Pelacarsen by using an ASO directed against the mRNA of apolipoprotein (a), reduces the production of apolipoprotein (a) in the liver and thus, the level of Lp (a).

A 6-month randomized, double-blind, parallel group and placebo-controlled study will include 60 patients with established cardiovascular disease (CVD) (including myocardial infarction, ischemic stroke or symptomatic peripheral artery disease) and Lp (a) levels above 700 mg / L.

The investigators will do anamnesis, targeted clinical examination, take blood samples for laboratory measurements, ultrasound measure endothelium-dependent dilatation of the brachial artery and beta stiffness of carotid arteries. Patients will be divided into two groups according to the randomization list. The first group will receive pelacarsen 80 mg subcutaneously and the second group will receive corresponding placebo. 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 the study. All patients will participate voluntarily, without pressure or inappropriate instigation and will give consent by signing the consent form.

The investigators hypotheses that in patients after myocardial infarction and high levels of Lp (a), Lp (a) and Lp (a) polymorphisms are associated with indicators of inflammation and structural-functional properties of the arterial wall; in patients after myocardial infarction and extremely high levels of Lp (a), pelacarsen reduces the value of Lp (a), indicators of inflammation and structural and functional involvement of the arterial wall; in patients after myocardial infarction and extremely high levels of Lp (a), the influence of pelacarsen 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

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 Locations

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

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:

  • concentration Lp (a) above 700 mg / L,
  • optimally treated risk factors for cardiovascular events according to currently valid guidelines,
  • history of myocardial infarction having occurred in the period 3 months to 10 years prior to the screening visit and / or
  • history of ischemic stroke having occurred in the period 3 months to 10 years prior to the screening visit and / or
  • clinically significant symptomatic peripheral artery disease.

Exclusion Criteria:

  • uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and / or diastolic blood pressure ≥ 100 mmHg),
  • heart failure New York Heart Association (NYHA) class IV,
  • history of malignancy of any organ system,
  • history of hemorrhagic stroke or other major bleeding,
  • platelet count <140,000 per mm3,
  • active liver disease or hepatic dysfunction (elevated transaminases above 3 times the norm, elevated bilirubin above 2 times the norm, elevated creatinine kinase above 3 times the norm),
  • significant kidney disease (oGFR <30 ml / min),
  • pregnant or nursing women,
  • life expectancy less than 5 years,
  • 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: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pelacarsen group (TQJ230)
The first group will receive 80 mg of pelacarsen every month subcutaneously for 6 months.
Drug: Pelacarsen (TQJ230)
The first group will receive pelacarsen. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery and beta stiffness of carotid arteries will be measured.
Placebo Comparator: Placebo group
The first group will receive 80 mg of placebo every month subcutaneously for 6 months.
Drug: Placebo
The second group will receive placebo. Blood samples from all patients will be drawn for laboratory measurements and genetics determination. Ultrasound measurement of endothelium-dependent dilatation of the brachial artery and beta stiffness of carotid arteries 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 pelacarsen on functional and morphological properties of arterial wall after 6 months
Time Frame: Baseline
Pelacarsen will improve functional and morphological properties of arterial wall. The investigators expect the improvements will be in correlation with the decrease of Lp (a) concentration.
Baseline

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., PhD, University Medical Centre Ljubljana (Slovenia)
  • Principal Investigator: Sabina Ugovšek, 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)

October 1, 2021

Primary Completion (Anticipated)

June 30, 2022

Study Completion (Anticipated)

October 1, 2022

Study Registration Dates

First Submitted

July 30, 2021

First Submitted That Met QC Criteria

July 30, 2021

First Posted (Actual)

August 6, 2021

Study Record Updates

Last Update Posted (Actual)

January 3, 2022

Last Update Submitted That Met QC Criteria

December 10, 2021

Last Verified

December 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PEMILA

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 Pelacarsen (TQJ230)

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Denmark

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe