Evolocumab for PCSK9 Lowering in Early Acute Sepsis (The PLEASe Study)

NCT03869073 | Unknown Phase 2 DMC FDA Drug

• 1 other identifier: H18-00917
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 3

Brief Summary

This study evaluates using evolocumab, a currently approved and marketed biologic drug, in a novel way. Patients who present to the emergency room or intensive care unit (ICU) with severe infection are eligible. Either the patient or their designated decision maker will be approached for consent. If they choose to participate they will be given either a single dose of evolocumab, a higher single dose of evolocumab,or a single dose of placebo. Participants will be followed during their stay in the ICU and will receive follow up phone calls at Day 28 and 90.

Conditions

Sepsis

Keywords

Bacterial; Infection; Blood; Systemic; ICU

Outcome Measures

Primary Outcomes (1)

• Area under the plasma LTA and LPS curves

  Determine whether evolocumab decreases plasma levels of bacterial LPS and LTA, at 6, 24, 48 and 72 hours, and day 7 by comparing the area under the operating curve between arms.

  7 days or less (as data is collected from participants only while they are admitted to critical care, they may be discharged or moved to a different ward before day 7 and therefore subsequent time points would be not be collected)

Secondary Outcomes (24)

• Levels of LDL-C

  7 days or less (as data is collected from participants only while they are admitted to critical care, they may be discharged or moved to a different ward before day 7 and therefore subsequent time points would be not be collected)

• Levels of cytokines IL-6, TNF-alpha and IL-8

  7 days or less (as data is collected from participants only while they are admitted to critical care, they may be discharged or moved to a different ward before day 7 and therefore subsequent time points would be not be collected)

• Concentration of circulating evolocumab and circulating free PCSK9 in septic patients

  7 days or less (may be discharged from critical care before day 7)

• Cmax of circulating evolocumab and circulating free PCSK9 in septic patients

  7 days or less (may be discharged from critical care before day 7)

• Days alive

  28 days or less (may be discharged from critical care before day 28)

Study Arms (3)

Low Dose

EXPERIMENTAL

This treatment arm will receive the highest dose of evolocumab currently marketed and approved: 420mg. The dose will be given at a single time point within 4 hours of randomization. The dose will be administered through three subcutaneous injections, each in a different quadrant of the abdomen.

Drug: Evolocumab

High Dose

EXPERIMENTAL

This treatment arm will receive double the highest dose of evolocumab currently marketed and approved: 840mg. The dose will be given at a single time point within 4 hours of randomization. The dose will be administered through three subcutaneous injections, each in a different quadrant of the abdomen.

Drug: Evolocumab

Placebo

PLACEBO COMPARATOR

This treatment arm will receive saline solution. The dose will be given at a single time point within 4 hours of randomization. The dose will be administered through three subcutaneous injections, each in a different quadrant of the abdomen.

Drug: Placebo

Interventions

Evolocumab DRUG

Three pre-filled shrouded syringes for subcutaneous injection in abdomen.

Also known as: Repatha

High Dose; Low Dose

Placebo DRUG

Preservative free 0.9% sodium chloride. Three pre-filled shrouded syringes for subcutaneous injection in abdomen.

Also known as: Saline

Placebo

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent
• At least 19 years of age
• Known or suspected infection
• AND one or more of the following organ dysfunctions judged due to sepsis:
• Cardiovascular- refractory hypotension (a systolic blood pressure (SBP) \< 90 mm Hg or mean arterial pressure (MAP) \< 60 mm Hg despite an IV fluid challenge of at least 30 ml/kg fluids), or use of vasopressor(s) to maintain SAP \> 90 mm Hg or MAP \> 60 mm Hg, or;
• Respiratory: PaO2/FiO2 \< 300 or PaO2/FiO2 \< 200 if lung is the only organ dysfunction or SaO2:FiO2 150

You may not qualify if:

• Known pregnancy
• Underlying severe congestive heart failure (New York Heart Association (NYHA) IV), severe COPD (need for chronic oxygen or mechanical ventilation), severe liver disease (Child-Pugh Class C), cancer requiring chemotherapy, or transplantation (bone marrow, heart, lung, liver, pancreas, or small bowel) in the past 6 months or likely within the next 6 months
• Previous episode of sepsis during that hospital admission
• Absolute Neutrophil Count \< 500/mm³
• CD4 count \< 50/mm³
• Treating physician deems aggressive care unsuitable (i.e. no commitment to active care)
• Participation in another interventional drug study within previous 1 month
• Allergic to the study drug or any of its components
• Lactation
• Have signed a Do No Resuscitate (DNR) Form

Sponsors & Collaborators

• University of British Columbia: lead

Study Sites (3)

Surrey Memorial Hospital

Surrey, British Columbia, V3V 1Z2, Canada

NOT YET RECRUITING

St. Paul's Hospital

Vancouver, British Columbia, V6Z 1Y6, Canada

RECRUITING

Vancouver General Hospital

Vancouver, British Columbia, V6Z 1Y6, Canada

NOT YET RECRUITING

Related Publications (8)

• Cirstea M, Walley KR, Russell JA, Brunham LR, Genga KR, Boyd JH. Decreased high-density lipoprotein cholesterol level is an early prognostic marker for organ dysfunction and death in patients with suspected sepsis. J Crit Care. 2017 Apr;38:289-294. doi: 10.1016/j.jcrc.2016.11.041. Epub 2016 Dec 7.

  PMID: 28013095 BACKGROUND

• Roveran Genga K, Lo C, Cirstea M, Zhou G, Walley KR, Russell JA, Levin A, Boyd JH. Two-year follow-up of patients with septic shock presenting with low HDL: the effect upon acute kidney injury, death and estimated glomerular filtration rate. J Intern Med. 2017 May;281(5):518-529. doi: 10.1111/joim.12601. Epub 2017 Mar 19.

  PMID: 28317295 BACKGROUND

• Levels JH, Abraham PR, van den Ende A, van Deventer SJ. Distribution and kinetics of lipoprotein-bound endotoxin. Infect Immun. 2001 May;69(5):2821-8. doi: 10.1128/IAI.69.5.2821-2828.2001.

  PMID: 11292694 BACKGROUND

• Levels JH, Abraham PR, van Barreveld EP, Meijers JC, van Deventer SJ. Distribution and kinetics of lipoprotein-bound lipoteichoic acid. Infect Immun. 2003 Jun;71(6):3280-4. doi: 10.1128/IAI.71.6.3280-3284.2003.

  PMID: 12761109 BACKGROUND

• Levels JH, Marquart JA, Abraham PR, van den Ende AE, Molhuizen HO, van Deventer SJ, Meijers JC. Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein. Infect Immun. 2005 Apr;73(4):2321-6. doi: 10.1128/IAI.73.4.2321-2326.2005.

  PMID: 15784577 BACKGROUND

• Topchiy E, Cirstea M, Kong HJ, Boyd JH, Wang Y, Russell JA, Walley KR. Lipopolysaccharide Is Cleared from the Circulation by Hepatocytes via the Low Density Lipoprotein Receptor. PLoS One. 2016 May 12;11(5):e0155030. doi: 10.1371/journal.pone.0155030. eCollection 2016.

  PMID: 27171436 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

• Boyd JH, Fjell CD, Russell JA, Sirounis D, Cirstea MS, Walley KR. Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis. J Innate Immun. 2016;8(2):211-20. doi: 10.1159/000442976. Epub 2016 Jan 13.

  PMID: 26756586 BACKGROUND

MeSH Terms

Conditions

Sepsis; Infections

Interventions

evolocumab; Sodium Chloride

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• John Boyd, MD

  University of British Columbia, Providence Health Care

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Genevieve L Rocheleau

CONTACT

604-682-2344; grocheleau@providencehealth.bc.ca

Lynda Lazosky

CONTACT

llazosky@providencehealth.bc.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Upon enrolling in the study participants will be randomized into one of three possible treatment arms: 420mg single dose at baseline, 840mg single dose at baseline, or placebo

Study Record Dates

• First Submitted: March 5, 2019
• First Posted: March 11, 2019
• Study Start: February 11, 2019
• Primary Completion: February 11, 2021
• Study Completion: February 11, 2021
• Last Updated: March 3, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3)