Treatment of Severe Infection With Antihyperlipidemia Drug

Study Overview
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Brief Summary
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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.

Detailed Description
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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. Microbial pathogenic lipids, namely LPS in gram negative bacteria, lipoteichoic acid in gram-positive bacteria, and phospholipomannan in fungi, are bound to lipids in the blood, causing an increase in PCSK9 in plasma. This led to the speculation that increased lipid clearance by the liver leads to increased LPS clearance affecting the process of sepsis and septic shock. Thus administering PCSK9 inhibitor leading to increase in lipids uptake by the liver would positively affect the septic patient. The benefit of inhibiting PCSK9 in sepsis is further strengthened by a study of Keith R et al examining septic patients who had at least one PCSK9 loss of function allele that showed increased survival over a 28-day period compared to those with gain of function allele. A study made by, Berger J M et al, on murines showed lack of benefit in septic mice when administering PCSK9 inhibitor adjacent to LPS injection peritoneally. In this study PCSK9 inhibitor was administered as a monotherapy while in studies showing benefit, antibiotics treatment was given. Furthermore the lack of benefit can be explained by the short duration between the induction of endotoxemia to PCSK9 inhibitors administration, inhibiting the binding of the inflammatory mediators to the lipid transports in the blood prior to the activation of the inflammatory response which is needed. As previously mentioned PCSK9 levels that were measured in past studies only increased after 4 hours from inflammatory induction and not immediately after the exposure to LPS. Due to the results of studies supporting the clinical benefit of PCSK9 inhibitors the investigators intend to conduct a study in septic patients and septic shock patients upon admission to the ICU. The PCSK9 inhibitor is a relatively safe drug with a small amount of mild adverse events. In the ODYSSEY LONG TERM study with 2341 patients, examining among others the safety of the PCSK9 inhibitor use, Alirocumab, at a dose of 150 mg had similar rates of adverse events between the treatment group and the placebo. The Alirocumab patients had higher rates than the placebo group with injection-site reactions, myalgia, neurocognitive events (amnesia, memory impairment, and confusional state), and ophthalmologic events at low rates. In a recent large meta-analysis examining adverse effects showed no statistical significant regarding neurocognitive events or diabetes. Same results were received in a small post marketing study finding most adverse events of flu like symptoms and myalgia without difference between placebo, Alirocumab 75 mg dose and the 150 mg dose. In order to validate the clinical use of PCSK9 inhibitor the investigators plan to administer 150 mg subcutaneous injection of Alirocumab upon admission to the ICU to patients diagnosed with sepsis or septic shock every two weeks. Two centers will be participating in the study from Israel.

Official Title
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PCSK9 Inhibitor: a New Tool to Fight Septic Shock

Conditions
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Sepsis, Septic Shock

Intervention / Treatment
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* Drug: Alirocumab Injectable Product
* Drug: Saline Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is admitted to the ICU Subject has a clinical diagnosis of sepsis or septic shock Exclusion Criteria: Liver function tests (aspartate aminotransferase and Alanine transaminase) above three times the normal levels. Creatinine clearance levels below 30. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: the study is a randomized placebo controlled double blinded study. the control group will be receiving placebo and the treatment group will be receiving the study drug.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: control group<br>The group will receive 2 ml' saline subcutaneous injection upon randomization when admitted to the ICU with the diagnosis of sepsis or septic shock | Drug: Saline Solution<br>* The placebo will be 2 ml' of 0.9% saline injected subcutaneously.<br>|
| Active Comparator: treatment group<br>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. | Drug: Alirocumab Injectable Product<br>* Alirocumab is an human monoclonal antibodies directed against Proprotein convertase subtilisin/kexin type 9 (PCSK9). It is administered once every two weeks subcutaneously.<br>* Other names: Praluent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival | We will measure the survival at 28 days | At 28 days from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length of stay in the ICU | Time until discharge from the ICU to the regular wards | 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 vasopressors | The time the patient requires the supports of vasopressors drugs, mainly Norepinephrine | From the date of documented use of vasopressor drugs until the documented cessation of this therapy assessed up to 24 month | 
| Time on mechanical ventilation | The time the patient requires the support of mechanical ventilation | From the date of documented use of mechanical ventilation until the documented discontinuation of mechanical ventilation assessed up to 24 month | 
| Levels of inflammatory mediators | The levels of C reactive protein and leukocytes during a time frame | At the time of randomization once every day assessed up to 28 days | 
| Lactate levels | The time it takes for lactate levels to return to normal | At the time of randomization and 3 times a day until the documentation of normal lactate values assessed up to 28 days | 
| Length of hospital stay | The time the patient is hospitalized in the ICU and the wards | From the time of randomization until first documentation of hospital discharge or date of death from any cause assessed up to 24 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, septic shock, PCSK9 INHIBITOR