PCSK9 Inhibitor: a New Tool to Fight Septic Shock
试验速览
- 阶段
- 2 期
- 入组人数
- 712
- 试验地点
- 1
- 主要终点
- survival
研究概览
简要总结
Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors increase LDL receptors by decreasing its degradation. In sepsis the pathogenic substances, endotoxin, lipoteichoic acid, phospholipomannan are the main cause of the ongoing inflammation that causes the severe damage and outcome. these substances are removed from the blood by the LDL receptors. By administering PCSK9 inhibitors to patients with sepsis/septic shock this inflammatory response can be stopped and by doing so improve the patients outcome.
详细描述
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection with a high mortality rate. The main causative agents in the ICU to cause sepsis and septic shock are gram negative bacteria Klebsiella spp., Escherichia coli (E. coli), and Pseudomonas aeruginosa (P. aeruginosa) and gram positive Staphylococcus aureus (S. aureus), Streptococcus pyogenes (S. pyogenes). The role of bacterial endotoxin is known to be central to development of septic shock in gram-negative bacterial sepsis. Gram negative bacteria's membranes are made of lipopolysaccharides (LPS), the endotoxin. The pattern recognition receptor for LPS is Toll-like receptor 4 (TLR4), upon activation initiates the inflammatory cascade.
In past studies it was demonstrated that despite the lack of LPS on gram positive bacteria, TLR4 mutant's mice had higher bacterial burden and lower survivability suggesting a role in the inflammatory cascade of TLR4 despite the lack of LPS.
Super antigen bind directly to the major histocompatibility complex II (MHC-II) receptor and T cell receptor causing a massive T cell activation bypassing the antigen presenting cell leading to cytokine storm.
Studies on murine, measuring the levels of LDL during inflammation, demonstrated a high level of LDL in the blood due to suppression of LDL receptor proteins in the liver. Proprotein convertase subtilisin kexin 9 (PCSK9) is a serine protease secreted by the liver binding to the LDL receptor and enhancing its degradation causing the increase of LDL levels in the blood. In the absence of PCSK9, the number of LDL receptors on the liver cell surface increases and more circulating LDL is removed from the plasma.
PCSK9 is found to increase during inflammation. Grefhorst A et al, demonstrated that administration of recombinant PCSK9 to mice reduced hepatic LDL receptors. Based on that finding, Kenneth R. Feingold et al, conducted a study administering lipopolysaccharides (LPS) to mice intra peritoneal, measuring the levels of hepatic LDL receptor protein levels, and PCSK9 messenger ribonucleic acid (mRNA) levels in the liver and in the kidneys. There was an increase in the PCSK9 levels within 4 hours in response to LPS and in response to several other mechanisms causing systemic inflammation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
the study drug and placebo will be identical arriving from the manufacturing company as a clear fluid for subcutaneous injection of 2 ml'. both arms, the control and intervention, will receive identical subcutaneous injections. the randomization will be prior to recruitment in the pharmacy. At the end of the study the outcomes assessor will be exposed to the data unblended.
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject is admitted to the ICU
- •Subject has a clinical diagnosis of sepsis or septic shock
排除标准
- •Liver function tests (aspartate aminotransferase and Alanine transaminase) above three times the normal levels.
- •Creatinine clearance levels below
- •Life expectancy below 28 days due to terminal illness.
- •Moribund condition with life expectancy of less than 24 hours.
- •Pregnancy or lactating women.
- •Known hypersensitivity to the study drug.
- •Grade IV peripheral edema at time of randomization.
研究组 & 干预措施
control group
The group will receive 2 ml' saline subcutaneous injection upon randomization when admitted to the ICU with the diagnosis of sepsis or septic shock
干预措施: Saline Solution (Drug)
treatment group
The group will receive a 2 ml' subcutaneous injection of the study drug Alirocumab 150 mg', upon randomization when admitted to the ICU with the diagnosis of sepsis or septic shock.
干预措施: Alirocumab Injectable Product (Drug)
结局指标
主要结局
survival
时间窗: At 28 days from randomization
We will measure the survival at 28 days
次要结局
- Time on vasopressors(From the date of documented use of vasopressor drugs until the documented cessation of this therapy assessed up to 24 month)
- Levels of inflammatory mediators(At the time of randomization once every day assessed up to 28 days)
- Length of hospital stay(From the time of randomization until first documentation of hospital discharge or date of death from any cause assessed up to 24 month)
- Length of stay in the ICU(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 month)
- Time on mechanical ventilation(From the date of documented use of mechanical ventilation until the documented discontinuation of mechanical ventilation assessed up to 24 month)
- Lactate levels(At the time of randomization and 3 times a day until the documentation of normal lactate values assessed up to 28 days)
研究者
Rozman Ziv
Principal investigator
Wolfson Medical Center