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

Randomized, Double-blind, Placebo-controlled Phase 2a Trial of Efficacy and Safety of Evolocumab for PCSK9 Lowering in Early Acute Sepsis

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.

Study Overview

• Status: Unknown
• Conditions: Sepsis
• Intervention / Treatment: Drug: Evolocumab; Drug: Placebo

Detailed Description

Evolocumab is currently approved and marketed in USA and Canada for lowering cholesterol levels. Evolocumab is an anti-PSCK9 monoclonal antibody, and functions by binding PSCK9 (an inhibitor of LDL removal) and blocking its function. Evidence suggests that since evolocumab increases the removal rate of low-density lipoproteins from the body, it might also help increase the removal of bacterial components that are attached to circulating lipids during sepsis. Quickly removing these bacterial components could prevent a strong and rapid immune response that often leads to organ failure and death in sepsis patients.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Surrey, British Columbia, Canada, V3V 1Z2
      • Not yet recruiting
      • Surrey Memorial Hospital
      • Principal Investigator: Gregory Haljan, MD
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Recruiting
      • St. Paul's Hospital
      • Principal Investigator: John Boyd, MD
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Not yet recruiting
      • Vancouver General Hospital
      • Principal Investigator: Donald Griesdale, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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:

  1. 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;
  2. Respiratory: PaO2/FiO2 < 300 or PaO2/FiO2 < 200 if lung is the only organ dysfunction or SaO2:FiO2 150

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Dose; 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; Three pre-filled shrouded syringes for subcutaneous injection in abdomen.; Other Names: Repatha
Experimental: High Dose; 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; Three pre-filled shrouded syringes for subcutaneous injection in abdomen.; Other Names: Repatha
Placebo Comparator: Placebo; 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; Preservative free 0.9% sodium chloride. Three pre-filled shrouded syringes for subcutaneous injection in abdomen.; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of LDL-C	Measure levels (concentration; e.g. ug/mL) of low-density lipoprotein-cholesterol (LDL-C) at 24, 48, and 72 hours, and day 7, and compare area under the plasma cytokine 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)
Levels of cytokines IL-6, TNF-alpha and IL-8	Measure levels (concentration; e.g. ug/mL) of cytokines (IL-6, TNF-alpha and IL-8) at 24, 48, and 72 hours, and day 7, and compare area under the plasma cytokine 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)
Concentration of circulating evolocumab and circulating free PCSK9 in septic patients	Assess the concentration (e.g. umol/L) of circulating evolocumab and free (unbound by antibody) PCSK9 in evolocumab-treated patients with sepsis and compare to placebo controls.	7 days or less (may be discharged from critical care before day 7)
Cmax of circulating evolocumab and circulating free PCSK9 in septic patients	Assess the Cmax of circulating evolocumab and free (unbound by antibody) PCSK9 in evolocumab-treated patients with sepsis and compare to placebo controls.	7 days or less (may be discharged from critical care before day 7)
Days alive	Determine if changes in days alive over 28 days are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in 28-day mortality	Determine whether differences in mortality rates at 28 days exist between treatment arms.	28 days
Level of organ dysfunction	Determine if changes in days free of organ dysfunction (cardiovascular, respiratory, renal, hematologic, and hepatic) over 28 days are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Level of organ support	Determine if changes in days free of organ support (vasopressor, ventilation and renal replacement therapy (RRT)) over 28 days are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: lactate	Determine if changes in plasma lactate levels (mmol/L) are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: norepinephrine dose	Determine if changes in norepinephrine levels (mcg/min) are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: mean arterial pressure	Determine if changes in mean arterial pressure levels (mm Hg) are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: heart rate	Determine if changes in heart rate (beats per minute) are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: respiratory rate	Determine if changes in respiratory rate (breaths per minute) are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: temperature	Determine if changes in temperature (degrees Celsius) are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: fluid balance	Determine if changes in fluid balance (Liters) are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: urine output	Determine if changes in urine output (Liters) are associated with treatment arm.	28 days or less (may be discharged from critical care before day 28)
Safety outcomes: Number of treatment-related adverse events as ranked by severity	Monitor and count by category, and evaluate severity and seriousness of any adverse events related to the intervention that occurs in this critical and previously untested population.	Day 1 to Day 90
Safety outcomes: changes in blood cell counts	Document changes in blood cell counts (cells/ml) including white blood cells, red blood cells, and platelets, and determine whether clinically significant changes are associated with treatment.	28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in coagulation	Document changes in coagulation of blood by measuring Prothrombin Time (PT) and Partial Thromboplastin Time (PTT). Both measurements determine time to clotting (in seconds) of different clotting factors and are then used to calculate International Normalized Ratio (INR) which helps monitor effects of blood thinning medication, and determine whether clinically significant changes are associated with treatment.	28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in blood analytes	Document changes in concentration (e.g. umol/mL) of blood analytes, including hemoglobin, glucose, glycated hemoglobin, potassium, sodium, chloride, bicarbonate, creatinine, calcium, triponine, magnesium, aminotransferase, and alanine aminotransferase, and determine whether clinically significant changes are associated with treatment.	28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in urine density	Document changes in urine specific gravity (density relative to water) and determine whether clinically significant changes are associated with treatment.	28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in urine pH	Document changes in urine pH and determine whether clinically significant changes are associated with treatment.	28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in concentration of ketones in urine	Document changes in concentration of ketones (e.g. umol/L) in the urine and determine whether clinically significant changes are associated with treatment.	28 days or less (may be discharged from critical care before day 28)
Safety outcomes: document other urine abnormalities if required	Document presence of blood, nitrites, bacteria, or urinary casts in the urine (yes or no) and determine whether clinically significant changes are associated with treatment.	28 days or less (may be discharged from critical care before day 28)

Collaborators and Investigators

• Sponsor: University of British Columbia
• Investigators: Principal Investigator: John Boyd, MD, University of British Columbia, Providence Health Care

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: PLoS One. 2016;11(7):e0160326.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2019
• Primary Completion (Anticipated): February 11, 2021
• Study Completion (Anticipated): February 11, 2021

Study Registration Dates

• First Submitted: March 5, 2019
• First Submitted That Met QC Criteria: March 7, 2019
• First Posted (Actual): March 11, 2019

Study Record Updates

• Last Update Posted (Actual): March 3, 2020
• Last Update Submitted That Met QC Criteria: March 2, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Infection; ICU; Blood; Systemic; Bacterial
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: H18-00917

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes