Effect of Lipoprotein(a) Elimination by Lipoprotein Apheresis on Cardiovascular Outcomes (MultiSELECt)

A European Multicenter Study on the Effect of Lipoprotein(a) Elimination by Lipoprotein Apheresis on Cardiovascular Outcomes

This multicenter multinational prospective two-arm matched-pair observational study aims to establish a prospective comparison of active lipoprotein apheresis treatment approved and conducted according to German guidelines for the indication of elevated Lp(a) versus a maximum tolerated lipid-lowering therapy as standard care. Due to the prospective character and the inclusion of a control arm, this will be the first clinical study that can confirm the relevance of the established approach to use lipoprotein apheresis in those subjects and its effects to reduce the individual cardiovascular risk. The optimized management of subjects in the control group (not receiving lipoprotein apheresis) will also help to clarify the controversial issue, to which extent intensive medical care per se can influence the occurence of subsequent cardiovascular events. Primary objective of the trial is to evaluate the clinical benefit of Lp(a) reduction using lipoprotein apheresis on myocardial infarction, PCI, CABG, fatal and non- fatal stroke, transient ischemic attack, interventional or surgical revascularization of peripheral arteries and death from cardiovascular disease. The primary objective of this study evaluates the clinical benefit of weekly lipoprotein apheresis in subjects with progressive cardiovascular disease, as accepted by the German Federal Joint Committee as indication for subjects with elevated Lp(a). Comparator will be matched subjects under maximum tolerated lipid lowering therapy without access to lipoprotein apheresis treatment. The clinical benefit will be defined as the reduction of the composite endpoint of major adverse cardiovascular events (MACE), defined as either myocardial infarction, PCI, CABG, fatal and non-fatal stroke, transient ischemic attack or death from cardiovascular disease over a period of at least 2 years after completion of visit 1b and until at least 60 events of the primary end-point occurred in group B. If the number of at least 60 documented primary endpoint events within 2 years of the completion of enrolment did not occur, the study will continue until this number of primary endpoint events has accumulated.

Study Overview

• Status: Recruiting
• Conditions: Lipoprotein Types--Lp System Lp(A) Hyperlipoproteinemia

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

• Study Contact: Name: Anne Kaul; Phone Number: 3075 +49 351 458; Email: info@multiselect-trial.eu
• Study Contact Backup: Name: Bernd Hohenstein, MD; Phone Number: 3075 +49 351 458; Email: info@multiselect-trial.eu

Study Locations

• Germany
  • Bad Oeynhausen, Germany, 32545
    • Recruiting
    • Herz- und Diabeteszentrum NRW Universitätsklinik der Ruhr-Universität Bochum Klinik für Kardiologie
    • Contact: Klaus Peter Mellwig, MD
  • Bochum, Germany, 44789
    • Recruiting
    • Dialyse am Kortumpark
    • Contact: Velthof Ansgar, MD
  • Göttingen, Germany, 37075
    • Recruiting
    • Nephrologisches Zentrum Göttingen
    • Contact: Volker Schettler, MD
  • Meißen, Germany, 01662
    • Recruiting
    • PHV Dialysezentrum
    • Contact: Beate Schulze, MD
  • Muenchen, Germany, 80337
    • Recruiting
    • Klinikum der Universität München Campus Innenstadt
    • Contact: Anja Vogt, MD
  • Muenchen, Germany, 81337
    • Recruiting
    • Klinikum der Universität München Campus Grosshadern
    • Contact: Klaus Parhofer, MD
  • Potsdam, Germany, 14471
    • Recruiting
    • Dialysezentrum Potsdam
    • Contact: Jens Ringel, MD
  • Reinbek, Germany, 21465
    • Recruiting
    • Nierenzentrum Reinbek
    • Contact: Markus Reinbek, MD
  • Rostock, Germany, 18059
    • Recruiting
    • Nephrocare Rostock GmbH Medizinisches Versorgungszentrum Südstadt
    • Contact: Wolfgang Ramlow, MD
  • Villingen-Schwenningen, Germany, 78052
    • Recruiting
    • Nephrologisches Zentrum
    • Contact: Bernd Hohenstein, MD
    • Contact: Email: hohenstein@nephrologie-vs.de
  • Zwickau, Germany, 08060
    • Recruiting
    • Heinrich Braun Klinikum
    • Contact: Jens Gerth, MD
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Recruiting
      • University Hospital Carl Gustav Carus
      • Contact: Ulrich Julius, MD; Phone Number: +493514582176; Email: ulrich.julius@ukdd.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

All participants have to be 18 years or older and need to be intellectually capable to understand and follow the study protocol. All subjects have to present with progressive cardiovascular disease and need to fulfill the criteria fixed in the recommendations by the German Joint Federal Committee (in German: "Gemeinsamer Bundesausschuss"; see section 1.2). In addition, a TEC has to verify presence of the treatment indication and will be blinded with respect to subject's group assignment. Apheresis subjects (group A) will be included in chronological order, since this will most likely reflect the natural distribution of disease in the general population. Control subjects (group B) will then be matched to the lipoprotein apheresis subjects entering the study.

Description

Inclusion Criteria:

1. Age 18 - 70
2. Male or female
3. Written informed consent
4. Lipoprotein(a) > 60 mg/dL, or > 120 nmol/L using an alternative laboratory method
5. Corrected Low-density lipoprotein cholesterol < 100 mg/dL (2.6 mmol/l) during 3 months prior to study enrolment.

6. Established cardiovascular disease with disease progression indicated by one major cardiovascular event, which might be either

   • myocardial infarction
   • PCI
   • CABG
   • Stroke
   • or revascularization of peripheral arteries using PTA, stenting or bypass surgery

   (with or without subsequent cardiovascular events/interventions) despite adequately controlled cardiovascular risk factors* occuring within the last 2 years prior to enrolment

   (*Hypertension, Diabetes, tobacco consumption, LDL Cholesterol)

7. Platelet aggregation inhibitors or systemic anticoagulation according to cardiologic indication
8. Positive recommendation by central Trial Expert Committee

Exclusion Criteria:

1. Previous lipoprotein apheresis therapy
2. Triglyceride concentrations ≥ 250 mg/dL (2.8 mmol/L)
3. Known homozygous or compound heterozygous familial hypercholesterolemia
4. Known type III hyperlipoproteinemia
5. Pregnancy, breast feeding
6. Active smoking, defined as any inhaled tobacco consumption with in the last 3 months
7. Uncontrolled hypertension (>160/90 mmHg)
8. Active malignant disease
9. Planned major surgical procedures
10. Current participation in an interventional trial
11. Contraindication for apheresis therapy (e. g. necessity of ACE inhibitor therapy)
12. CKD stages IV and V
13. Diabetes mellitus

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Group A: Lipoprotein apheresis subjects; Established cardiovascular disease with disease progression indicated by one major cardiovascular event. With or without subsequent cardiovascular events/interventions, despite adequately controlled cardiovascular risk factors occuring within the last 2 years prior to enrolment. Corrected Low-density lipoprotein cholesterol < 100 mg/dL (2.6 mmol/l) during 3 months prior to study enrolment. Additional lipoprotein apheresis is established following enrolment using the following established systems: Dextran-sulfate adsorption (DSA) from plasma and whole blood, Heparin-induced LDL precipitation apheresis (HELP®), Polyacrylate adsorption from whole blood and simple DFPP (DALI® and Monet®), ApoB100-immunoadsorption (TheraSorbLDL®, Temperature-optimized double filtration plasmapheresis (DFPP).
Group B: Control group; Established cardiovascular disease with disease progression indicated by one major cardiovascular event. With or without subsequent cardiovascular events/interventions, despite adequately controlled cardiovascular risk factors occuring within the last 2 years prior to enrolment. Corrected Low-density lipoprotein cholesterol < 100 mg/dL (2.6 mmol/l) during 3 months prior to study enrolment. The control group will not undergo a sham apheresis procedure. It is an open trial.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary end-point is an at least 10 % reduction of the proportion of events	The primary end-point is an at least 10 % reduction of the proportion of events regarding the composite end-point consisting either of myocardial infarction, PCI, CABG, fatal and non-fatal stroke, transient ischemic attack, interventional or surgical revascularization of peripheral arteries or death from cardiovascular disease (or any combination of these) at the final visit.	2 years of follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
An at least 10 % reduction of the proportion of events	An at least 10 % reduction of the proportion of events regarding the composite endpoint of cardiovascular death, major coronary event, cerebrovascular accidents and stroke.	2 years of follow-up
An at least 10 % reduction of the proportion of events	An at least 10 % reduction of the proportion of events regarding the composite endpoint of cardiovascular death, major coronary events and all cerebrovascular events.	2 years of follow-up
An at least 10 % reduction of the proportion of events regarding the composite Secondary endpoints of the Trial	An at least 10 % reduction of the proportion of events regarding the composite endpoint of CV death, non-fatal MI, documented unstable angina that requires admission into a hospital, all revascularization (including both coronary and non-coronary) occurring at least 30 days after the MACE event, the rate of in-stent restenosis and non-fatal stroke.	2 years of follow-up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of individual endpoints	Reduction of individual endpoints at the final visit, reported as % reduction of the number of cumulated and individual events; death from any cause,; CHD death,; CV death,; MI,; documented unstable angina that requires admission into a hospi-tal,; all coronary revascularization occurring at least 30 days after a prior MACE event:either PCI orCABG; all revascularization (including both coronary and non-coronary) occurring at least 30 days after a prior MACE event,; in-stent restenosis rate,; stroke,; transient ischemic attack,; Percentage of subjects achieving a mean reduction of Lp(a) of 60% or more; Mean reduction of Lp(a); Percentage of subjects achieving mean LDL-C reduction of 60 % or more; Number of apheresis related side effects; Quality of life	2 years of follow-up

Collaborators and Investigators

• Sponsor: Technische Universität Dresden
• Collaborators: Kaneka Pharma Europe N.V.
• Investigators: Principal Investigator: Bernd Hohenstein, MD, Technische Universitat Dresden

Publications and helpful links

Helpful Links

• Study Homepage

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: May 26, 2016
• First Submitted That Met QC Criteria: June 6, 2016
• First Posted (Estimate): June 7, 2016

Study Record Updates

• Last Update Posted (Actual): May 2, 2022
• Last Update Submitted That Met QC Criteria: April 29, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Lipoprotein(a); lipoprotein/lipid apheresis; CV disease
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias
• Other Study ID Numbers: TUD-LPA16-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided