Treatment of Severe Infection With Antihyperlipidemia Drug

NCT03634293 | Unknown Phase 2 DMC

• 1 other identifier: PCSK9 administration in sepsis
• Study Type: interventional
• Target: 712
• Locations: 1 country
• Sites: 1

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.

Conditions

Sepsis; Septic Shock

Keywords

sepsis; septic shock; PCSK9 INHIBITOR

Outcome Measures

Primary Outcomes (1)

• survival

  We will measure the survival at 28 days

  At 28 days from randomization

Secondary Outcomes (6)

• 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 vasopressors

  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

  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

  At the time of randomization once every day assessed up to 28 days

• Lactate levels

  At the time of randomization and 3 times a day until the documentation of normal lactate values assessed up to 28 days

Study Arms (2)

control group

PLACEBO COMPARATOR

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

treatment group

ACTIVE COMPARATOR

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

Interventions

Alirocumab Injectable Product DRUG

Alirocumab is an human monoclonal antibodies directed against Proprotein convertase subtilisin/kexin type 9 (PCSK9). It is administered once every two weeks subcutaneously.

Also known as: Praluent

treatment group

Saline Solution DRUG

The placebo will be 2 ml' of 0.9% saline injected subcutaneously.

control group

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject is admitted to the ICU
• Subject has a clinical diagnosis of sepsis or septic shock

You may not qualify if:

• 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.

Sponsors & Collaborators

• Wolfson Medical Center: lead
• Assaf-Harofeh Medical Center: collaborator
• Sanofi: collaborator

Study Sites (1)

Eduard Ilgiyaev

Rishon LeZiyyon, 70300, Israel

Location

Related Publications (20)

• 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.

  PMID: 26903338 BACKGROUND

• 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.

  PMID: 10340174 BACKGROUND

• 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.

  PMID: 9237759 BACKGROUND

• 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.

  PMID: 24193365 BACKGROUND

• 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.

  PMID: 14742522 BACKGROUND

• 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.

  PMID: 8611169 BACKGROUND

• 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.

  PMID: 17215125 BACKGROUND

• 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.

  PMID: 24625727 BACKGROUND

• 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.

  PMID: 27478094 BACKGROUND

• 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.

  PMID: 18638454 BACKGROUND

• 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.

  PMID: 18354138 BACKGROUND

• 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.

  PMID: 25320231 BACKGROUND

• 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.

  PMID: 27496869 BACKGROUND

• 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.

  PMID: 26252194 BACKGROUND

• 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.

  PMID: 25320235 BACKGROUND

• 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.

  PMID: 28600283 BACKGROUND

• 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.

  PMID: 25773378 BACKGROUND

• 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.

  PMID: 29223954 BACKGROUND

• 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.

  PMID: 28738813 BACKGROUND

• 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.

  PMID: 28304224 BACKGROUND

MeSH Terms

Conditions

Sepsis; Shock, Septic

Interventions

alirocumab; Saline Solution

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Ziv Rosman, MD

  Wolfson Medical Center

  STUDY DIRECTOR

Central Study Contacts

Ziv Rosman, MD

CONTACT

5462626025; zivr@wmc.gov.il

arie soroksky, MD

CONTACT

35028770; aries@wmc.gov.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: 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.

Study Record Dates

• First Submitted: July 30, 2018
• First Posted: August 16, 2018
• Study Start: January 1, 2019
• Primary Completion: January 1, 2021
• Study Completion: February 1, 2021
• Last Updated: August 16, 2018

Record last verified: 2018-08

Locations

IL (1)