Kinetic Study of Lp(a) and PCSK9 in Humans (HuLaUP)

A Kinetic Study of Lipoprotein in Humans for a Better Understanding of Lipoprotein(a) Metabolism Under PCSK9 Variations (Hu-La-u-P Study)

The aim is to study the relationship between lipoprotein(a) [Lp(a)] and PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) in humans with a kinetic study of lipoproteins in patients with dramatic increase of Lp(a) and controls.

Study Overview

• Status: Completed
• Conditions: Cholesterol; Metabolic Disorder; Lipoproteinemia
• Intervention / Treatment: Other: infusion of tracer [5,5,5-2H3] -L-leucine

Detailed Description

Elevated plasma levels of lipoprotein(a) [Lp(a)] are independently associated with an increased risk of cardiovascular diseases (CVD). Recently an unexpected and significant 15 to 30 % reduction of Lp(a) was reported with PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors. The relation between Lp(a) and PCSK9 are unclear and debated.

Kinetic studies of lipoprotein are an important tool to decipher the complexity of apolipoprotein metabolism in human. The comparison of apoprotein(a) and PCSK9 kinetic parameters of patients with extreme lipid disorder link to PCSK9 and apo(a) will allow to better understand the impact of PCSK9 on apo(a). From one previous in vitro study, the hypothesize is that PCSK9 increases the production rate and the assembly of Lp(a).

The objectives are to explore the relationship between the plasma concentration of PCSK9 and apo(a) production rate as well as the impact on the catabolic rate. Patients with extreme Lp(a) levels and healthy controls will be explored by performing a continuous infusion of deuterated leucine for 14 hours. LC/MS-MS will be used to analyze the samples and kinetic data of apo(a) and PCSK9 will be generated from a compartmental model. Tracer enrichment analysis could be complicated for proteins with low plasma concentrations as PCSK9. This issue will be solved with SPE and/or immune affinity concentration techniques. Non-parametrical test and multivariate analysis will be use to describe the relationship between these two variables.

This study will provide new knowledge on Lp(a) and PCSK9 metabolism and their interactions in humans.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Nantes, France, 44093
    • Nantes university hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age: 18 to 75 years
• For subjects in the "Control" group: Patients with no major LDL-cholesterol deficiency (patients eligible for LDL-apheresis, eg LDL-C> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a) <50 mg / dl or
• For subjects in the "high-dose" group: Patients with no major LDL-cholesterol abnormalities (LDL-apheresis eligible patients, eg LDL-C> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a)> 80 mg / dl Whenever possible, groups will be balanced for age, sex, familial forms of hypercholesterolemia and their major groups of mutations.

Exclusion Criteria:

• Patients treated with PCSK9 antibodies.
• Patients with acute illness and considered incompatible by the investigator
• Uncontrolled diabetes (HbA1c> 8.5%)
• Severe hepatic insufficiency
• Creatinine clearance <30 ml / min
• Patients not covered by a social security scheme or beneficiary of such a scheme
• Patients unable to understand and / or sign consent
• Pregnant or lactating women
• Minors
• Majors under guardianship or trusteeship or safeguard of justice

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Control group; Patients with no major LDL cholesterol abnormalities (patients eligible for LDL-apheresis, eg LDL-C> 200 mg / dL for secondary prevention and 300 mg / LDL-C) dl in primary prevention)) and a level of Lp (a) <50 mg / dl	Other: infusion of tracer [5,5,5-2H3] -L-leucine; A bolus of 6ml of [5,5,5-2H3] -L-leucine tracers will be performed followed by an infusion of 90 ml of [5,5,5-2H3] -L-leucine infused over 14 hours. This tracer participates in protein synthesis and especially in the synthesis of all apolipoproteins and PCSK9. Blood samples will be taken at T0, T2min, T5min, T10 minutes, T30 minutes and then every hour until 14 hours (a total of 240 ml of blood will be collected) to measure the stable tracer enrichment in the proteins of interest.
Experimental: High-dose group; Patients with no major LDL-cholesterol abnormalities (LDL-apheresis eligible patients, eg LDL-C> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a)> 80 mg / dl	Other: infusion of tracer [5,5,5-2H3] -L-leucine; A bolus of 6ml of [5,5,5-2H3] -L-leucine tracers will be performed followed by an infusion of 90 ml of [5,5,5-2H3] -L-leucine infused over 14 hours. This tracer participates in protein synthesis and especially in the synthesis of all apolipoproteins and PCSK9. Blood samples will be taken at T0, T2min, T5min, T10 minutes, T30 minutes and then every hour until 14 hours (a total of 240 ml of blood will be collected) to measure the stable tracer enrichment in the proteins of interest.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To study in humans by a study of the kinetics of apo (a), the relationships between the metabolism of Lp (a) and the plasma levels of PCSK9.	Correlation between PCSK9 plasma levels and apo (a) production rate (fractional production rate (RPF) and absolute production rate (APR)) in patients with Lp (a)> 80 mg / dl and control subjects with Lp (a) levels <30mg / dl.; Correlation between PCSK9 plasma levels and apo (a) fractional clearance rate (FCR) in patients with Lp (a)> 80 mg / dl and control subjects with Lp (a) levels <30mg / dl.	14 hours after leucine infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the impact of PCSK9 metabolism on metabolic parameters of Lp (a).	Correlation between the PCSK9 (fractional production rate (RPF) and absolute production rate (APR) synthesis rate and the rate of synthesis and degradation of apo (a) (fractional production rate (FPR) and absolute production rate ( APR)) and fractional clearance rate (FCR) in patients with Lp (a)> 80 mg / dl and control subjects with Lp (a) <30mg / dl.	14 hours after leucine infusion
To evaluate the impact of PCSK9 metabolism on metabolic parameters of Lp	Correlation between PCSK9 (fractional clearance rate (FCR)) and the rate of synthesis and degradation of apo (fractional production rate (RPF) and absolute production rate (APR)) and (fractional clearance rate spleen (FCR)) in patients with Lp (a)> 80 mg / dl and control subjects with Lp (a) <30mg / dl.	14 hours after leucine infusion
To measure the impact of PCSK9 metabolism on metabolic parameters of Lp	Correlation between the production and degradation rates of Lp (a), PCSK9 and apoB100 in patients with Lp (a)> 80 mg / dl and control subjects with Lp (a) ) <30 mg / dl.	14 hours after leucine infusion

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Collaborators: Centre de Recherche en Nutrition Humaine Ouest (CRNH)

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2020
• Primary Completion (Actual): December 23, 2021
• Study Completion (Actual): December 23, 2021

Study Registration Dates

• First Submitted: September 2, 2019
• First Submitted That Met QC Criteria: January 28, 2020
• First Posted (Actual): January 29, 2020

Study Record Updates

• Last Update Posted (Actual): February 23, 2022
• Last Update Submitted That Met QC Criteria: February 22, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases
• Other Study ID Numbers: RC18_0281

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No