Clinical trial NCT03869073: Evolocumab for PCSK9 Lowering in Early Acute Sepsis (The PLEASe Study)
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
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Sepsis
Keywords: Bacterial
Infection
Blood
Systemic
ICU
Lead sponsor: University of British Columbia
Sponsor class: OTHER
First posted: 2019-03-11
Enrollment: 36
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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.

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:

  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

Primary outcomes:
measure: Area under the plasma LTA and LPS curves
timeFrame: 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 outcomes:
measure: Levels of LDL-C
timeFrame: 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 of cytokines IL-6, TNF-alpha and IL-8
timeFrame: 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: Concentration of circulating evolocumab and circulating free PCSK9 in septic patients
timeFrame: 7 days or less (may be discharged from critical care before day 7)
measure: Cmax of circulating evolocumab and circulating free PCSK9 in septic patients
timeFrame: 7 days or less (may be discharged from critical care before day 7)
measure: Days alive
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in 28-day mortality
timeFrame: 28 days
measure: Level of organ dysfunction
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Level of organ support
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in Vitals: lactate
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in Vitals: norepinephrine dose
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in Vitals: mean arterial pressure
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in Vitals: heart rate
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in Vitals: respiratory rate
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in Vitals: temperature
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in Vitals: fluid balance
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Changes in Vitals: urine output
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Safety outcomes: Number of treatment-related adverse events as ranked by severity
timeFrame: Day 1 to Day 90
measure: Safety outcomes: changes in blood cell counts
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Safety outcomes: changes in coagulation
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Safety outcomes: changes in blood analytes
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Safety outcomes: changes in urine density
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Safety outcomes: changes in urine pH
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Safety outcomes: changes in concentration of ketones in urine
timeFrame: 28 days or less (may be discharged from critical care before day 28)
measure: Safety outcomes: document other urine abnormalities if required
timeFrame: 28 days or less (may be discharged from critical care before day 28)
Other outcomes:
Locations:
city: Surrey
country: Canada
facility: Surrey Memorial Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
Study officials:
affiliation: University of British Columbia, Providence Health Care
name: John Boyd, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.