Long-term Characterization of Lipoprotein Apheresis Technologies for Individual Device Adaption (LOLIDA) (LOLIDA)

Lipoprotein apheresis is often applied as the final treatment of patient with severe and medication resistant dyslipidemia and progressive atherosclerosis. The high effectiveness of lipoprotein apheresis to improve the patient's metabolic situation and thereby strongly minimize the incidence of cardiovascular events was confirmed by a variety of studies.

While in the past years, mostly patients with severe homo- or heterozygous familial hypercholesterolemia (FH) or otherwise highly elevated LDL-cholesterol were subjected to lipoprotein apheresis, currently the major indication for lipoprotein apheresis is a critical elevated plasma level of lipoprotein (a) [Lp(a)] in patients with severe cardiovascular events. Even if it is now widely accepted that Lp(a) is an independent risk factor for cardiovascular diseases due to its pro-atherogenic potential, the exact molecular mechanisms by which Lp(a) contributes to the atherosclerotic process remain unclear. Despite rigorous reduction of plasma Lp(a)-levels during lipoprotein apheresis newly occurring cardiovascular events cannot prevented in all patients. Specific pleiotropic effects of apheresis technologies are supposed to be critically involved in the clinical outcome. By measurement of a wide variety of cardio-metabolic biomarkers playing a role in inflammation, endothelial dysfunction, lipid metabolism or blood pressure regulation during repeated Lp(a) lowering by various apheresis methods may allow the identification of clusters of risk factors determining clinical outcome and give the biological basement for an optimized individual lipoprotein apheresis therapy.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Lipoproteinemia; Apheresis Related Complication
• Intervention / Treatment: Device: Dextran sulfate absorption (LIPOSORBER® D - Kaneka Pharma Europe NV); Device: Lipid filtration (Octo Nova®, Diamed Medizintechnik); Device: Direct absorption of lipoproteins (DALI®; ADS 4008, Fresenius); Device: Therasorb (TheraSorb® - LDL adsorbers, Miltenyi Biotec)

Detailed Description

Aims The aim of the proposed project is the investigation of Lp(a) kinetics in patients under regular lipoprotein apheresis with regard to short- and long-term changes in diverse clinical parameter contributing to atherogenesis by applying different LA methods. The expected gain of knowledge might result in an improvement of patient stratification and the individual assignment to a well-tolerated and optimal apheresis procedure, which is essential for therapy outcome and improvement of the patient's life quality.

Specific questions Depending on the apheresis procedure, does the repeated use of lipoprotein apheresis therapy in patients with pathological high Lp(a) plasma concentration cause reproducible and stable changes in biomarkers of cardial dysfunction, inflammatory state, oxidative stress, endothelial dysfunction, and cardial fibrosis?

Is there an association between Lp(a)- and biomarker dynamics during long-term lipoprotein apheresis?

It is possible to identify high-risk cluster of biomarkers in patients with newly occurring cardio-vascular events after the onset of lipoprotein apheresis?

(I) Set up of examination cohorts and basal characterization of the patients

Set up of 4 patient cohorts of 15 individuals each who are currently treated with apheresis therapy:

1. Dextran sulfate absorption (LIPOSORBER® D - Kaneka Pharma Europe NV)
2. Lipid filtration (Octo Nova®, Diamed Medizintechnik)
3. Direct absorption of lipoproteins (DALI®; ADS 4008, Fresenius)
4. Therasorb (TheraSorb® - LDL adsorbers, Miltenyi Biotec)

The observation period will cover 80 weekly apheresis sessions with plasma samples taken directly before, after and seven days after the first, the 20th, the 40th, the 60th and the 80th apheresis sessions. Parameters of routine clinical chemistry (see below) will be used for characterization of patients. Samples will be collected directly before and after apheresis and before subsequent apheresis throughout the entire observation period.

Carotid intima-media thickness (IMT) is a well-accepted non-invasive marker of subclinical atherosclerosis and end-organ damage. Measurement of IMT by intravascular ultrasound can be used to evaluate the effectiveness of different therapy modalities on the progression of atherosclerotic-based diseases.

(II) Basal clinical characterization

Parameters for clinical characterization: age, weight, height, body mass index, waist- and hip circumferences, waist to hip ratio, waist to height ratio, blood pressure

(III) Record of parameters of routine clinical chemistry

Total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol, triglycerides (TG), ALAT, γ-GT, blood cell count, serum creatinine

(IV) Analysis of parameters for evaluation of cardio-metabolic risk profile

Biomarkers of cardiac dysfunction NT-proANP, NT-proBNP

Biomarkers characterizing inflammatory state and oxidative Stress CRP, MPO, AOPP, IL-6, TNF-α, GDF-15, Pentraxin-3

Biomarkers of endothelial dysfunction and atherosclerosis NT-proCNP, CD146, Lysophosphatidylcholine (LPC)

Evaluation of fibrosis markers Gal-3, sSt2, (soluble form of ST2 [IL1RL1]), Fibrinogen

Functional assay for thrombus formation Platelet function test

Data management and statistics:

The project will be supervised by an independent biometrician throughout all stages. All data will be stored in a central database. Responsible for completeness, accuracy, reliability, and validation are the applicants and the delegated biometrician. Original data in electronic form will be kept for 10 years on storage devices with backups performed every 14 days.

For statistical analysis the current version of SPSS package will be employed. Data will be analyzed by different models of multivariate and univariate analyses of variance.

Were applicable a principal component analysis will be used. Correlation analyses between clinical variables and plasma lipidome were performed using Spearman's nonparametric rank correlation coefficient Rho. For all statistical procedures a p-value of 0.05 or less will be considered significant.

Benefit and perspective The proposed project consists of aspects with direct clinical relevance as well as with fundamental importance in medical research on the field of lipoprotein apheresis. Important scientific findings are expected regarding the individual risk for the progression of atherosclerotic diseases in patients during apheresis therapy which can pave the way towards a patient-optimized appliance of apheresis technologies. In addition to individualized therapy, the expected result concerning pro-atherogenic biomarkers might further elucidate underlying processes in Lp(a) pathology.

• Study Type: Observational
• Enrollment (Anticipated): 500

Contacts and Locations

• Study Contact: Name: Jürgen Gräßler, MD; Phone Number: 3691 +49351458; Email: Juergen.Graessler@uniklinikum-dresden.de
• Study Contact Backup: Name: Nikolaos Perakakis, MD; Phone Number: 13651 +49351458; Email: Nikolaos.Perakakis@uniklinikum-dresden.de

Study Locations

• Germany
  • Dresden, Germany, 01307
    • Recruiting
    • Carl Gustav Carus University Hospital Dresden, Technische Universität Dresden,
    • Contact: Marko Käppler; Phone Number: 18623 +49 351 458; Email: marko.kaeppler@uniklinikum-dresden.de
    • Principal Investigator: Jürgen Gräßler, MD
    • Sub-Investigator: Nikolaos Perakakis, MD
    • Principal Investigator: Ulrich Julius, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients undegoing lipoprotein apheresis based on the above described inclusion and exclusion criteria

Description

Inclusion Criteria:

Inclusion criteria for lipoprotein apheresis in accordance with regulations of the German Federal Joint Committee of physicians and medical insurance companies (G-BA; Gemeinsamer Bundesausschuss der Ärzte und Krankenkassen) are either:

• homozygous familial hypercholesterolemia or
• severe hypercholesterolemia in patients after 12 month of dietary intervention and maximal lipid-lowering drug therapy with regard on the overall risk profile of the patient or
• Lp(a) levels > 120 nmol/L in patients with progressive cardiovascular disease after unsuccessful intervention with established methods of treatment

Mandatory for inclusion of patients for lipoprotein apheresis is a comprehensive cardiological, angiological and lipidological pre-examination.

(Deutsches Ärzteblatt 100 (2003), 1595; Deutsches Ärzteblatt 105 (2008), 1778)

Exclusion Criteria:

• Patients after transplantation
• Immunosuppressive therapy (including intake of glucocorticoids within four weeks prior to sample collection)
• uncontrolled arterial hypertension (>180/110 mm Hg)
• epilepsy
• acute malignant and infectious diseases
• liver disease (gamma-GT > 1.8 μmol/L×s, ALAT > 1.5 μmol/L×s),
• severe renal dysfunction (GFR < 30 ml/min per 1.73 m2)
• smoking
• hypersensitivity against heparin
• participation in another study

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Dextran sulfate absorption (LIPOSORBER® D - Kaneka Pharma Europe NV); Apheresis therapy	Device: Dextran sulfate absorption (LIPOSORBER® D - Kaneka Pharma Europe NV); Lipoprotein apheresis Method I
Lipid filtration (Octo Nova®, Diamed Medizintechnik); Apheresis therapy	Device: Lipid filtration (Octo Nova®, Diamed Medizintechnik); Lipoprotein apheresis Method II
Direct absorption of lipoproteins (DALI®; ADS 4008, Fresenius); Apheresis therapy	Device: Direct absorption of lipoproteins (DALI®; ADS 4008, Fresenius); Lipoprotein apheresis Method III
Therasorb (TheraSorb® - LDL adsorbers, Miltenyi Biotec); Apheresis therapy	Device: Therasorb (TheraSorb® - LDL adsorbers, Miltenyi Biotec); Lipoprotein apheresis Method IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of new biomarkers for individualized assignment of lipoprotein apheresis technology	Characterization of short- and long-term effects of repeated lipoprotein apheresis by dextran sulfate absorption (LIPOSORBER® D - Kaneka Pharma Europe NV), lipid filtration (Octo Nova®, Diamed Medizintechnik), direct absorption of lipoproteins (DALI®; ADS 4008, Fresenius), and TheraSorb™ (Miltenyi Biotec GmbH, Germany) on cardio-metabolic risk factors, including biomarkers of heart failure, inflammation, oxidative stress, endothelial dysfunction and fibrosis.	10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recordings of newly manifested cardiovascular events	Recording of newly manifested cardiovascular events: Ischemic or haemorrhagic stroke; Myocardial infarction; New manifestation of angina pectoris; Implantation of cardiovascular stents; Cases of death due to cardiovascular complications	10 years

Collaborators and Investigators

• Sponsor: Technische Universität Dresden

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2014
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: December 20, 2021
• First Submitted That Met QC Criteria: December 20, 2021
• First Posted (Actual): January 10, 2022

Study Record Updates

• Last Update Posted (Actual): January 10, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Lipoprotein apheresis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Anticoagulants; Plasma Substitutes; Blood Substitutes; Dextrans
• Other Study ID Numbers: EK403102014

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