Clinical trial NCT03634293: Treatment of Severe Infection With Antihyperlipidemia Drug
Official title: PCSK9 Inhibitor: a New Tool to Fight Septic Shock
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Sepsis
Septic Shock
Keywords: sepsis
septic shock
PCSK9 INHIBITOR
Lead sponsor: Wolfson Medical Center
Sponsor class: OTHER_GOV
Collaborators: name: Assaf-Harofeh Medical Center
name: Sanofi
First posted: 2018-08-16
Enrollment: 712
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: * 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.

Primary outcomes:
measure: survival
timeFrame: At 28 days from randomization
Secondary outcomes:
measure: Length of stay in the ICU
timeFrame: 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
measure: Time on vasopressors
timeFrame: From the date of documented use of vasopressor drugs until the documented cessation of this therapy assessed up to 24 month
measure: Time on mechanical ventilation
timeFrame: From the date of documented use of mechanical ventilation until the documented discontinuation of mechanical ventilation assessed up to 24 month
measure: Levels of inflammatory mediators
timeFrame: At the time of randomization once every day assessed up to 28 days
measure: Lactate levels
timeFrame: At the time of randomization and 3 times a day until the documentation of normal lactate values assessed up to 28 days
measure: Length of hospital stay
timeFrame: From the time of randomization until first documentation of hospital discharge or date of death from any cause assessed up to 24 month
Other outcomes:
Locations:
city: Rishon LeZion
country: Israel
facility: Eduard Ilgiyaev
Study officials:
affiliation: Wolfson Medical Center
name: Ziv Rosman, MD
role: STUDY_DIRECTOR
References:
citation: Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
citation: Sriskandan S, Cohen J. Gram-positive sepsis. Mechanisms and differences from gram-negative sepsis. Infect Dis Clin North Am. 1999 Jun;13(2):397-412. doi: 10.1016/s0891-5520(05)70082-9.
citation: Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997 Jul 24;388(6640):394-7. doi: 10.1038/41131.
citation: Ramachandran G. Gram-positive and gram-negative bacterial toxins in sepsis: a brief review. Virulence. 2014 Jan 1;5(1):213-8. doi: 10.4161/viru.27024. Epub 2013 Nov 5.
citation: Branger J, Knapp S, Weijer S, Leemans JC, Pater JM, Speelman P, Florquin S, van der Poll T. Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice. Infect Immun. 2004 Feb;72(2):788-94. doi: 10.1128/IAI.72.2.788-794.2004.
citation: Liao W, Rudling M, Angelin B. Endotoxin suppresses rat hepatic low-density lipoprotein receptor expression. Biochem J. 1996 Feb 1;313 ( Pt 3)(Pt 3):873-8. doi: 10.1042/bj3130873.
citation: Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007 Feb;32(2):71-7. doi: 10.1016/j.tibs.2006.12.008. Epub 2007 Jan 9.
citation: Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014 Mar 14;114(6):1022-36. doi: 10.1161/CIRCRESAHA.114.301621.
citation: Gouni-Berthold I, Descamps OS, Fraass U, Hartfield E, Allcott K, Dent R, Marz W. Systematic review of published Phase 3 data on anti-PCSK9 monoclonal antibodies in patients with hypercholesterolaemia. Br J Clin Pharmacol. 2016 Dec;82(6):1412-1443. doi: 10.1111/bcp.13066. Epub 2016 Oct 4.
citation: Feingold KR, Moser AH, Shigenaga JK, Patzek SM, Grunfeld C. Inflammation stimulates the expression of PCSK9. Biochem Biophys Res Commun. 2008 Sep 19;374(2):341-4. doi: 10.1016/j.bbrc.2008.07.023. Epub 2008 Jul 16.
citation: Grefhorst A, McNutt MC, Lagace TA, Horton JD. Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J Lipid Res. 2008 Jun;49(6):1303-11. doi: 10.1194/jlr.M800027-JLR200. Epub 2008 Mar 19.
citation: dos Santos C, Marshall JC. Bridging lipid metabolism and innate host defense. Sci Transl Med. 2014 Oct 15;6(258):258fs41. doi: 10.1126/scitranslmed.3010501.
citation: Norata GD, Tavori H, Pirillo A, Fazio S, Catapano AL. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc Res. 2016 Oct;112(1):429-42. doi: 10.1093/cvr/cvw194. Epub 2016 Aug 5.
citation: Walley KR, Francis GA, Opal SM, Stein EA, Russell JA, Boyd JH. The Central Role of Proprotein Convertase Subtilisin/Kexin Type 9 in Septic Pathogen Lipid Transport and Clearance. Am J Respir Crit Care Med. 2015 Dec 1;192(11):1275-86. doi: 10.1164/rccm.201505-0876CI.
citation: Walley KR, Thain KR, Russell JA, Reilly MP, Meyer NJ, Ferguson JF, Christie JD, Nakada TA, Fjell CD, Thair SA, Cirstea MS, Boyd JH. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med. 2014 Oct 15;6(258):258ra143. doi: 10.1126/scitranslmed.3008782.
citation: Berger JM, Loza Valdes A, Gromada J, Anderson N, Horton JD. Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice. J Lipid Res. 2017 Aug;58(8):1661-1669. doi: 10.1194/jlr.M076844. Epub 2017 Jun 9.
citation: Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1489-99. doi: 10.1056/NEJMoa1501031. Epub 2015 Mar 15.
citation: Karatasakis A, Danek BA, Karacsonyi J, Rangan BV, Roesle MK, Knickelbine T, Miedema MD, Khalili H, Ahmad Z, Abdullah S, Banerjee S, Brilakis ES. Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta-Analysis of 35 Randomized Controlled Trials. J Am Heart Assoc. 2017 Dec 9;6(12):e006910. doi: 10.1161/JAHA.117.006910.
citation: Choi J, Khan AM, Jarmin M, Goldenberg N, Glueck CJ, Wang P. Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab and evolocumab, a post-commercialization study. Lipids Health Dis. 2017 Jul 24;16(1):141. doi: 10.1186/s12944-017-0493-7.
citation: Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.