A Kinetic Study of Lipoprotein in Humans for a Better Understanding of Lipoprotein(a) Metabolism Under PCSK9 Variations (Hu-La-u-P Study)
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 2
- 主要终点
- 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.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
- •Majors under guardianship or trusteeship or safeguard of justice
结局指标
主要结局
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.
时间窗: 14 hours after leucine infusion
1. 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. 2. 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.
次要结局
- To measure the impact of PCSK9 metabolism on metabolic parameters of Lp(14 hours after leucine infusion)
- To evaluate the impact of PCSK9 metabolism on metabolic parameters of Lp(14 hours after leucine infusion)
- To evaluate the impact of PCSK9 metabolism on metabolic parameters of Lp (a).(14 hours after leucine infusion)