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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low Dose | Experimental | 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. |
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| High Dose | Experimental | 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. |
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| Placebo | Placebo Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Evolocumab | Drug | Three pre-filled shrouded syringes for subcutaneous injection in abdomen. |
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| 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) |
| 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) |
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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:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Genevieve L Rocheleau | Contact | 604-682-2344 | 64888 | grocheleau@providencehealth.bc.ca |
| Lynda Lazosky | Contact | llazosky@providencehealth.bc.ca |
| Name | Affiliation | Role |
|---|---|---|
| John Boyd, MD | University of British Columbia, Providence Health Care | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Surrey Memorial Hospital | Not yet recruiting | Surrey | British Columbia | V3V 1Z2 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28013095 | Background | 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. | |
| 28317295 | Background |
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| ID | Term |
|---|---|
| D018805 | Sepsis |
| D007239 | Infections |
| ID | Term |
|---|---|
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C577155 | evolocumab |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
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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
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| Placebo | Drug | Preservative free 0.9% sodium chloride. Three pre-filled shrouded syringes for subcutaneous injection in abdomen. |
|
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| 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) |
| St. Paul's Hospital | Recruiting | Vancouver | British Columbia | V6Z 1Y6 | Canada |
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| Vancouver General Hospital | Not yet recruiting | Vancouver | British Columbia | V6Z 1Y6 | Canada |
|
| 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. |
| 11292694 | Background | 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. |
| 12761109 | Background | 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. |
| 15784577 | Background | 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. |
| 27171436 | Background | 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. |
| 25320235 | Background | 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. |
| 26756586 | Background | 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. |
| D017670 |
| Sodium Compounds |