Back to resultsEvolocumab for PCSK9 Lowering in Early Acute Sepsis (The PLEASe Study) (PLEASe)
Primary Purpose
Sepsis
Status
Unknown status
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Evolocumab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Sepsis focused on measuring Bacterial, Infection, Blood, Systemic, ICU
Eligibility 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:
- 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
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
Sites / Locations
- Surrey Memorial Hospital
- St. Paul's HospitalRecruiting
- Vancouver General Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Low Dose
High Dose
Placebo
Arm Description
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.
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
Days alive
Determine if changes in days alive over 28 days are associated with treatment arm.
Changes in 28-day mortality
Determine whether differences in mortality rates at 28 days exist between treatment arms.
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.
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.
Changes in Vitals: lactate
Determine if changes in plasma lactate levels (mmol/L) are associated with treatment arm.
Changes in Vitals: norepinephrine dose
Determine if changes in norepinephrine levels (mcg/min) are associated with treatment arm.
Changes in Vitals: mean arterial pressure
Determine if changes in mean arterial pressure levels (mm Hg) are associated with treatment arm.
Changes in Vitals: heart rate
Determine if changes in heart rate (beats per minute) are associated with treatment arm.
Changes in Vitals: respiratory rate
Determine if changes in respiratory rate (breaths per minute) are associated with treatment arm.
Changes in Vitals: temperature
Determine if changes in temperature (degrees Celsius) are associated with treatment arm.
Changes in Vitals: fluid balance
Determine if changes in fluid balance (Liters) are associated with treatment arm.
Changes in Vitals: urine output
Determine if changes in urine output (Liters) are associated with treatment arm.
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.
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.
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.
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.
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.
Safety outcomes: changes in urine pH
Document changes in urine pH and determine whether clinically significant changes are associated with treatment.
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.
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.
Full Information
NCT ID
NCT03869073
First Posted
March 5, 2019
Last Updated
March 2, 2020
Sponsor
University of British Columbia
1. Study Identification
Unique Protocol Identification Number
NCT03869073
Brief Title
Evolocumab for PCSK9 Lowering in Early Acute Sepsis (The PLEASe Study)
Acronym
PLEASe
Official Title
Randomized, Double-blind, Placebo-controlled Phase 2a Trial of Efficacy and Safety of Evolocumab for PCSK9 Lowering in Early Acute Sepsis
Study Type
Interventional
2. Study Status
Record Verification Date
March 2020
Overall Recruitment Status
Unknown status
Study Start Date
February 11, 2019 (Actual)
Primary Completion Date
February 11, 2021 (Anticipated)
Study Completion Date
February 11, 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of British Columbia
4. Oversight
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
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sepsis
Keywords
Bacterial, Infection, Blood, Systemic, ICU
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderOutcomes Assessor
Allocation
Randomized
Enrollment
36 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Low Dose
Arm Type
Experimental
Arm Description
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.
Arm Title
High Dose
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Evolocumab
Other Intervention Name(s)
Repatha
Intervention Description
Three pre-filled shrouded syringes for subcutaneous injection in abdomen.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Saline
Intervention Description
Preservative free 0.9% sodium chloride. Three pre-filled shrouded syringes for subcutaneous injection in abdomen.
Primary Outcome Measure Information:
Title
Area under the plasma LTA and LPS curves
Description
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.
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)
Secondary Outcome Measure Information:
Title
Levels of LDL-C
Description
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.
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)
Title
Levels of cytokines IL-6, TNF-alpha and IL-8
Description
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.
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)
Title
Concentration of circulating evolocumab and circulating free PCSK9 in septic patients
Description
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.
Time Frame
7 days or less (may be discharged from critical care before day 7)
Title
Cmax of circulating evolocumab and circulating free PCSK9 in septic patients
Description
Assess the Cmax of circulating evolocumab and free (unbound by antibody) PCSK9 in evolocumab-treated patients with sepsis and compare to placebo controls.
Time Frame
7 days or less (may be discharged from critical care before day 7)
Title
Days alive
Description
Determine if changes in days alive over 28 days are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in 28-day mortality
Description
Determine whether differences in mortality rates at 28 days exist between treatment arms.
Time Frame
28 days
Title
Level of organ dysfunction
Description
Determine if changes in days free of organ dysfunction (cardiovascular, respiratory, renal, hematologic, and hepatic) over 28 days are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Level of organ support
Description
Determine if changes in days free of organ support (vasopressor, ventilation and renal replacement therapy (RRT)) over 28 days are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in Vitals: lactate
Description
Determine if changes in plasma lactate levels (mmol/L) are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in Vitals: norepinephrine dose
Description
Determine if changes in norepinephrine levels (mcg/min) are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in Vitals: mean arterial pressure
Description
Determine if changes in mean arterial pressure levels (mm Hg) are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in Vitals: heart rate
Description
Determine if changes in heart rate (beats per minute) are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in Vitals: respiratory rate
Description
Determine if changes in respiratory rate (breaths per minute) are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in Vitals: temperature
Description
Determine if changes in temperature (degrees Celsius) are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in Vitals: fluid balance
Description
Determine if changes in fluid balance (Liters) are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Changes in Vitals: urine output
Description
Determine if changes in urine output (Liters) are associated with treatment arm.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Safety outcomes: Number of treatment-related adverse events as ranked by severity
Description
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.
Time Frame
Day 1 to Day 90
Title
Safety outcomes: changes in blood cell counts
Description
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.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Safety outcomes: changes in coagulation
Description
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.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Safety outcomes: changes in blood analytes
Description
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.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Safety outcomes: changes in urine density
Description
Document changes in urine specific gravity (density relative to water) and determine whether clinically significant changes are associated with treatment.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Safety outcomes: changes in urine pH
Description
Document changes in urine pH and determine whether clinically significant changes are associated with treatment.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Safety outcomes: changes in concentration of ketones in urine
Description
Document changes in concentration of ketones (e.g. umol/L) in the urine and determine whether clinically significant changes are associated with treatment.
Time Frame
28 days or less (may be discharged from critical care before day 28)
Title
Safety outcomes: document other urine abnormalities if required
Description
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.
Time Frame
28 days or less (may be discharged from critical care before day 28)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility 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:
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
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Genevieve L Rocheleau
Phone
604-682-2344
Ext
64888
Email
grocheleau@providencehealth.bc.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Lynda Lazosky
Email
llazosky@providencehealth.bc.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Boyd, MD
Organizational Affiliation
University of British Columbia, Providence Health Care
Official's Role
Principal Investigator
Facility Information:
Facility Name
Surrey Memorial Hospital
City
Surrey
State/Province
British Columbia
ZIP/Postal Code
V3V 1Z2
Country
Canada
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gregory Haljan, MD
Facility Name
St. Paul's Hospital
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6Z 1Y6
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
John Boyd, MD
Facility Name
Vancouver General Hospital
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6Z 1Y6
Country
Canada
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Donald Griesdale, MD
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
28013095
Citation
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.
Results Reference
background
PubMed Identifier
28317295
Citation
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.
Results Reference
background
PubMed Identifier
11292694
Citation
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.
Results Reference
background
PubMed Identifier
12761109
Citation
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.
Results Reference
background
PubMed Identifier
15784577
Citation
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.
Results Reference
background
PubMed Identifier
27171436
Citation
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.
Results Reference
background
PubMed Identifier
25320235
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.
Results Reference
background
PubMed Identifier
26756586
Citation
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.
Results Reference
background
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Evolocumab for PCSK9 Lowering in Early Acute Sepsis (The PLEASe Study)
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