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

March 2, 2020 updated by: john boyd, University of British Columbia

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
36

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Canada
    • British Columbia
      • Surrey, British Columbia, Canada, V3V 1Z2
        • Not yet recruiting
        • Surrey Memorial Hospital
        • Principal Investigator:
          • Gregory Haljan, MD
      • Vancouver, British Columbia, Canada, V6Z 1Y6
        • Recruiting
        • St. Paul's Hospital
        • Principal Investigator:
          • John Boyd, MD
      • Vancouver, British Columbia, Canada, V6Z 1Y6
        • Not yet recruiting
        • Vancouver General Hospital
        • Principal Investigator:
          • Donald Griesdale, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Low Dose
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
Three pre-filled shrouded syringes for subcutaneous injection in abdomen.
Other Names:
  • Repatha
Experimental: High Dose
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
Three pre-filled shrouded syringes for subcutaneous injection in abdomen.
Other Names:
  • Repatha
Placebo Comparator: 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.
Drug: Placebo
Preservative free 0.9% sodium chloride. Three pre-filled shrouded syringes for subcutaneous injection in abdomen.
Other Names:
  • Saline

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Area under the plasma LTA and LPS curves
Time Frame: 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.
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Levels of LDL-C
Time Frame: 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.
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
Time Frame: 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.
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
Time Frame: 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.
7 days or less (may be discharged from critical care before day 7)
Cmax of circulating evolocumab and circulating free PCSK9 in septic patients
Time Frame: 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.
7 days or less (may be discharged from critical care before day 7)
Days alive
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in 28-day mortality
Time Frame: 28 days
Determine whether differences in mortality rates at 28 days exist between treatment arms.
28 days
Level of organ dysfunction
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Level of organ support
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: lactate
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: norepinephrine dose
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: mean arterial pressure
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: heart rate
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: respiratory rate
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: temperature
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: fluid balance
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Changes in Vitals: urine output
Time Frame: 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.
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
Time Frame: 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.
Day 1 to Day 90
Safety outcomes: changes in blood cell counts
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in coagulation
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in blood analytes
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in urine density
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in urine pH
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Safety outcomes: changes in concentration of ketones in urine
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)
Safety outcomes: document other urine abnormalities if required
Time Frame: 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.
28 days or less (may be discharged from critical care before day 28)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of British Columbia

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: John Boyd, MD, University of British Columbia, Providence Health Care

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
February 11, 2019

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 11, 2021

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 11, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 5, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 7, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 11, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 3, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 2, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • H18-00917

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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