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

• ClinicalTrials.gov Identifier: NCT03869073
• Recruitment Status: Unknown
• First Posted: March 11, 2019
• Last Update Posted: March 3, 2020
• Sponsor: University of British Columbia
• Information provided by (Responsible Party): john boyd, University of British Columbia

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Sepsis	Drug: Evolocumab; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 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
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-blind, Placebo-controlled Phase 2a Trial of Efficacy and Safety of Evolocumab for PCSK9 Lowering in Early Acute Sepsis
• Actual Study Start Date: February 11, 2019
• Estimated Primary Completion Date: February 11, 2021
• Estimated Study Completion Date: February 11, 2021

Arms and Interventions

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 Name: 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 Name: 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 Name: Saline

Outcome Measures

Primary Outcome Measures :

1. Area under the plasma LTA and LPS curves [ Time Frame: 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) ]
   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.

Secondary Outcome Measures :

1. Levels of LDL-C [ Time Frame: 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) ]
   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.
2. Levels of cytokines IL-6, TNF-alpha and IL-8 [ Time Frame: 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) ]
   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.
3. Concentration of circulating evolocumab and circulating free PCSK9 in septic patients [ Time Frame: 7 days or less (may be discharged from critical care before day 7) ]
   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.
4. Cmax of circulating evolocumab and circulating free PCSK9 in septic patients [ Time Frame: 7 days or less (may be discharged from critical care before day 7) ]
   Assess the Cmax of circulating evolocumab and free (unbound by antibody) PCSK9 in evolocumab-treated patients with sepsis and compare to placebo controls.
5. Days alive [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
   Determine if changes in days alive over 28 days are associated with treatment arm.
6. Changes in 28-day mortality [ Time Frame: 28 days ]
   Determine whether differences in mortality rates at 28 days exist between treatment arms.
7. Level of organ dysfunction [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
   Determine if changes in days free of organ dysfunction (cardiovascular, respiratory, renal, hematologic, and hepatic) over 28 days are associated with treatment arm.
8. Level of organ support [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
   Determine if changes in days free of organ support (vasopressor, ventilation and renal replacement therapy (RRT)) over 28 days are associated with treatment arm.
9. Changes in Vitals: lactate [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
   Determine if changes in plasma lactate levels (mmol/L) are associated with treatment arm.
10. Changes in Vitals: norepinephrine dose [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Determine if changes in norepinephrine levels (mcg/min) are associated with treatment arm.
11. Changes in Vitals: mean arterial pressure [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Determine if changes in mean arterial pressure levels (mm Hg) are associated with treatment arm.
12. Changes in Vitals: heart rate [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Determine if changes in heart rate (beats per minute) are associated with treatment arm.
13. Changes in Vitals: respiratory rate [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Determine if changes in respiratory rate (breaths per minute) are associated with treatment arm.
14. Changes in Vitals: temperature [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Determine if changes in temperature (degrees Celsius) are associated with treatment arm.
15. Changes in Vitals: fluid balance [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Determine if changes in fluid balance (Liters) are associated with treatment arm.
16. Changes in Vitals: urine output [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Determine if changes in urine output (Liters) are associated with treatment arm.
17. Safety outcomes: Number of treatment-related adverse events as ranked by severity [ Time Frame: Day 1 to Day 90 ]
    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.
18. Safety outcomes: changes in blood cell counts [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    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.
19. Safety outcomes: changes in coagulation [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    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.
20. Safety outcomes: changes in blood analytes [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    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.
21. Safety outcomes: changes in urine density [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Document changes in urine specific gravity (density relative to water) and determine whether clinically significant changes are associated with treatment.
22. Safety outcomes: changes in urine pH [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Document changes in urine pH and determine whether clinically significant changes are associated with treatment.
23. Safety outcomes: changes in concentration of ketones in urine [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    Document changes in concentration of ketones (e.g. umol/L) in the urine and determine whether clinically significant changes are associated with treatment.
24. Safety outcomes: document other urine abnormalities if required [ Time Frame: 28 days or less (may be discharged from critical care before day 28) ]
    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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Genevieve L Rocheleau; 604-682-2344 ext 64888; grocheleau@providencehealth.bc.ca

Contact: Lynda Lazosky; llazosky@providencehealth.bc.ca

Locations

Canada, British Columbia

Surrey Memorial Hospital; Not yet recruiting

Surrey, British Columbia, Canada, V3V 1Z2

Principal Investigator: Gregory Haljan, MD

St. Paul's Hospital; Recruiting

Vancouver, British Columbia, Canada, V6Z 1Y6

Principal Investigator: John Boyd, MD

Vancouver General Hospital; Not yet recruiting

Vancouver, British Columbia, Canada, V6Z 1Y6

Principal Investigator: Donald Griesdale, MD

Sponsors and Collaborators

University of British Columbia

Investigators

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

More Information

Publications:

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.

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.

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.

• Responsible Party: john boyd, Associate Professor, University of British Columbia
• ClinicalTrials.gov Identifier: NCT03869073
• Other Study ID Numbers: H18-00917
• First Posted: March 11, 2019
• Last Update Posted: March 3, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by john boyd, University of British Columbia:

Bacterial; Infection; Blood; Systemic; ICU

Additional relevant MeSH terms:

Sepsis; Toxemia; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Evolocumab; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents