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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Evolocumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bacterial, Infection, Blood, Systemic, ICU