Evolocumab for PCSK9 Lowering in Early Acute Sepsis (The PLEASe Study)
- Registration Number
- NCT03869073
- Lead Sponsor
- University of British Columbia
- 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 36
-
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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description High Dose Evolocumab 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. Placebo 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. Low Dose Evolocumab 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.
- Primary Outcome Measures
Name Time Method Area under the plasma LTA and LPS curves 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
Name Time Method Changes in 28-day mortality 28 days Determine whether differences in mortality rates at 28 days exist between treatment arms.
Level of organ support 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.
Changes in Vitals: norepinephrine dose 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.
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) 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 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.
Concentration of circulating evolocumab and circulating free PCSK9 in septic patients 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.
Safety outcomes: changes in urine density 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.
Safety outcomes: changes in urine pH 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.
Cmax of circulating evolocumab and circulating free PCSK9 in septic patients 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.
Days alive 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.
Level of organ dysfunction 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.
Changes in Vitals: lactate 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.
Changes in Vitals: heart rate 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.
Safety outcomes: changes in concentration of ketones in urine 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.
Changes in Vitals: temperature 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.
Safety outcomes: changes in blood cell counts 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.
Changes in Vitals: mean arterial pressure 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.
Changes in Vitals: respiratory rate 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.
Changes in Vitals: urine output 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.
Safety outcomes: Number of treatment-related adverse events as ranked by severity 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.
Changes in Vitals: fluid balance 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.
Safety outcomes: changes in coagulation 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.
Safety outcomes: changes in blood analytes 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.
Safety outcomes: document other urine abnormalities if required 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.
Trial Locations
- Locations (3)
Surrey Memorial Hospital
🇨🇦Surrey, British Columbia, Canada
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
St. Paul's Hospital
🇨🇦Vancouver, British Columbia, Canada