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

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.

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.

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