Clinical trial NCT04247048: Kinetic Study of Lp(a) and PCSK9 in Humans
Official title: A Kinetic Study of Lipoprotein in Humans for a Better Understanding of Lipoprotein(a) Metabolism Under PCSK9 Variations (Hu-La-u-P Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cholesterol; Metabolic Disorder
Lipoproteinemia
Lead sponsor: Nantes University Hospital
Sponsor class: OTHER
Collaborators: name: Centre de Recherche en Nutrition Humaine Ouest (CRNH)
First posted: 2020-01-29
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Kinetic study of lipoprotein metabolism with stable isotope tracers.
Primary purpose: OTHER

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 14 hours after leucine infusion
Secondary outcomes:
measure: To evaluate the impact of PCSK9 metabolism on metabolic parameters of Lp (a).
timeFrame: 14 hours after leucine infusion
measure: To evaluate the impact of PCSK9 metabolism on metabolic parameters of Lp
timeFrame: 14 hours after leucine infusion
measure: To measure the impact of PCSK9 metabolism on metabolic parameters of Lp
timeFrame: 14 hours after leucine infusion
Other outcomes:
Locations:
city: Nantes
country: France
facility: Nantes University Hospital
Study officials:
References: