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Alirocumab in Patients With Sepsis (PALMS)

Primary Purpose

Sepsis

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Alirocumab

Placebo

About this trial

This is an interventional treatment trial for Sepsis focused on measuring Sepsis, Septic shock, Respiratory failure, Vasopressors

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Suspected or confirmed infection as evidenced by ordering of blood cultures and administration of at least one antimicrobial agent
Acute respiratory or cardiovascular organ dysfunction attributed to sepsis as evidenced by at least one of the following requirements:
- Vasopressor Requirement - Continuous infusion of norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine or other vasopressor agents at any dose for greater than 1 hour and required to maintain a mean arterial pressure ≥ 65 mm Hg despite intravenous crystalloid infusion of at least 1000cc
- Respiratory Support Requirement - Acute hypoxemic respiratory failure defined as persistent hypoxemia requiring (1) intubation and mechanical ventilation, or (2) positive pressure ventilation via tight-fitting face mask or (3) high flow nasal cannula ≥ 45 liters per minute (LPM) flow and fraction of inspired oxygen (FiO2) ≥ 0.40
Anticipated or confirmed intensive care unit (ICU) admission

Exclusion Criteria:

Organ dysfunction present > 24 hours at time randomization
Limitations of care (defined as refusal of cardiovascular and respiratory support described under inclusion criteria) including "do not intubate" (DNI) status
Development of sepsis while in the hospital ( i.e not present on admission to hospital)
Chronic hypoxemia requiring supplemental non-invasive oxygen or home mechanical ventilation
Chronic cardiovascular failure requiring home mechanical hemodynamic support or home chemical hemodynamic support
Known allergy or known contraindication to alirocumab
Chronic disease/illness that, in the opinion of the site investigator, have an expected lifespan of < 30 days unrelated to current sepsis diagnosis (e.g, stage IV malignancy, neurodegenerative disease, etc.)
Requirement of more than 6 liters (L) nasal cannula (NC) if not receiving invasive mechanical ventilation
Pregnancy
Prisoner or incarceration
Current participation in another interventional pharmaceutical research study for sepsis
Inability or unwillingness of subject or legal surrogate/representative to give written informed consent

Sites / Locations

Grady Memorial HospitalRecruiting
Emory University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Alirocumab

Placebo

Arm Description

Critically ill participants with sepsis leading to cardiovascular and/or respiratory failure who are randomized to receive alirocumab.

Critically ill participants with sepsis leading to cardiovascular and/or respiratory failure who are randomized to receive a placebo to match alirocumab.

Outcomes

Primary Outcome Measures

Bacterial endotoxin level

Levels of bacterial endotoxin will be compared between study arms.

Lipoteichoic acid level

Levels of lipoteichoic acid will be compared between study arms.

Secondary Outcome Measures

Number of Vasopressor and Ventilation Free Days (VVFD)

The number of consecutive days free of vasopressors and mechanical ventilation (VVFD) will be compared between study arms. Ventilator and vasopressor free days will only accrue from the last date the participant was free of both ventilator and vasopressor support. Participants who die are scored zero VVFD, and participants who return to ventilator support or vasopressor support will have the VVFD count reset to zero days.

Mortality

The number of participants who die will be compared between study arms.

ICU Mortality

The number of participants who die while in the ICU will be compared between study arms.

Days in ICU

Length of stay in the ICU (measured in days) will be compared between study arms.

Days in Hospital

Length of stay in the hospital (measured in days) will be compared between study arms.

Tumor necrosis factor - alpha (TNF-alpha) Level

The level of the proinflammatory cytokine TNF will be compared between study arms. Higher levels of TNF are associated with poorer outcomes in patients with sepsis.

Interleukin-1 beta (IL-1 beta) Level

The level of the proinflammatory cytokine IL-1 will be compared between study arms. Higher levels of IL-1 are associated with poorer outcomes in patients with sepsis.

Interleukin-6 (IL-6) Level

The level of the proinflammatory cytokine IL-6 will be compared between study arms. Higher levels of IL-6 are associated with poorer outcomes in patients with sepsis.

Interleukin-10 (IL-10) Level

The level of the proinflammatory cytokine IL-10 will be compared between study arms. Higher levels of IL-10 are associated with poorer outcomes in patients with sepsis.

Full Information

NCT ID

NCT05469347

First Posted

July 19, 2022

Last Updated

February 17, 2023

Sponsor

Jonathan Sevransky

Collaborators

Regeneron Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT05469347

Brief Title

Alirocumab in Patients With Sepsis

Acronym

PALMS

Official Title

PCSK9 and Lipid Metabolism in Sepsis (PALMS) : A Two-center, Phase 1b Randomized, Placebo-controlled, Double-blind, Clinical Trial of Alirocumab in Patients With Sepsis

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

January 4, 2023 (Actual)

Primary Completion Date

September 2023 (Anticipated)

Study Completion Date

September 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Jonathan Sevransky

Collaborators

Regeneron Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to determine whether the drug alirocumab, which may lower cholesterol, can reduce the amount of inflammation caused by an infection that has caused either low blood pressure or difficulty breathing. Participants will be randomized to receive a single IV infusion of alirocumab or a placebo.

Detailed Description

Sepsis is an inflammatory syndrome with life threatening organ dysfunction resulting from a dysregulated host response to infection. The global burden is estimated to exceed 15 million cases annually. In the United States, the incidence is increasing and currently there are more 1,750,000 cases each year, with more than half requiring intensive care unit (ICU) admission. Further, sepsis cases account for 30%- 50% of all hospital deaths, making it the third leading cause of death in the United States, and is the most expensive reason for hospitalization with annual expenditures exceeding $20 billion. Notably, even among those that do survive, many endure significant reductions in physical, emotional and cognitive quality of life. New therapeutic approaches to reduce the high morbidity and mortality of sepsis are needed. Current management strategies focus on early aggressive fluid resuscitation, blood pressure support with vasopressors, early appropriate antibiotics, and the identification and control of infected sites. Though outcomes have improved with the bundled deployment of these strategies, mortality remains high at 20 - 30%. Despite over a hundred phase 2 and phase 3 clinical trials of pharmacological agents with the potential to improve sepsis outcomes, only antibiotics have demonstrated reproducible benefits. Despite decades of research, no specific treatment of the dysregulated host response has proven effective. There is strong biologic plausibility to modulate the PCSK9 pathway in sepsis patients. Alirocumab is a PCSK9 inhibitor that has been shown to reduce LDL cholesterol in normal volunteers and in patients with familial hypercholesterolemia. Patients admitted to a study site hospital with sepsis or septic shock associated with cardiovascular or respiratory failure will be considered for enrollment. Those meeting eligibility criteria and providing consent for study participation will be randomized to receive alirocumab or a placebo, administered once via IV over an approximately 30 ± 10 minute infusion. Participants will be followed for 180 days.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sepsis

Keywords

Sepsis, Septic shock, Respiratory failure, Vasopressors

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Alirocumab

Arm Type

Experimental

Arm Description

Critically ill participants with sepsis leading to cardiovascular and/or respiratory failure who are randomized to receive alirocumab.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Critically ill participants with sepsis leading to cardiovascular and/or respiratory failure who are randomized to receive a placebo to match alirocumab.

Intervention Type

Drug

Intervention Name(s)

Alirocumab

Other Intervention Name(s)

Praluent

Intervention Description

A 600 mg dose of alirocumab (which is equivalent to 8mg/kg for a 75kg patient) will be administered once via IV over an approximately 30 ± 10 minute infusion using an infusion pump.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

A placebo to match a 600 mg dose of alirocumab will be administered once via IV over an approximately 30 ± 10 minute infusion using an infusion pump.

Primary Outcome Measure Information:

Title

Bacterial endotoxin level

Description

Levels of bacterial endotoxin will be compared between study arms.

Time Frame

Hour 120

Title

Lipoteichoic acid level

Description

Levels of lipoteichoic acid will be compared between study arms.

Time Frame

Hour 120

Secondary Outcome Measure Information:

Title

Number of Vasopressor and Ventilation Free Days (VVFD)

Description

Time Frame

Up to Day 30

Title

Mortality

Description

The number of participants who die will be compared between study arms.

Time Frame

Day 30

Title

ICU Mortality

Description

The number of participants who die while in the ICU will be compared between study arms.

Time Frame

Up to Day 180

Title

Days in ICU

Description

Length of stay in the ICU (measured in days) will be compared between study arms.

Time Frame

Up to Day 180

Title

Days in Hospital

Description

Length of stay in the hospital (measured in days) will be compared between study arms.

Time Frame

Up to Day 180

Title

Tumor necrosis factor - alpha (TNF-alpha) Level

Description

The level of the proinflammatory cytokine TNF will be compared between study arms. Higher levels of TNF are associated with poorer outcomes in patients with sepsis.

Time Frame

Hour 120

Title

Interleukin-1 beta (IL-1 beta) Level

Description

The level of the proinflammatory cytokine IL-1 will be compared between study arms. Higher levels of IL-1 are associated with poorer outcomes in patients with sepsis.

Time Frame

Hour 120

Title

Interleukin-6 (IL-6) Level

Description

The level of the proinflammatory cytokine IL-6 will be compared between study arms. Higher levels of IL-6 are associated with poorer outcomes in patients with sepsis.

Time Frame

Hour 120

Title

Interleukin-10 (IL-10) Level

Description

The level of the proinflammatory cytokine IL-10 will be compared between study arms. Higher levels of IL-10 are associated with poorer outcomes in patients with sepsis.

Time Frame

Hour 120

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Suspected or confirmed infection as evidenced by ordering of blood cultures and administration of at least one antimicrobial agent Acute respiratory or cardiovascular organ dysfunction attributed to sepsis as evidenced by at least one of the following requirements: Vasopressor Requirement - Continuous infusion of norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine or other vasopressor agents at any dose for greater than 1 hour and required to maintain a mean arterial pressure ≥ 65 mm Hg despite intravenous crystalloid infusion of at least 1000cc Respiratory Support Requirement - Acute hypoxemic respiratory failure defined as persistent hypoxemia requiring (1) intubation and mechanical ventilation, or (2) positive pressure ventilation via tight-fitting face mask or (3) high flow nasal cannula ≥ 45 liters per minute (LPM) flow and fraction of inspired oxygen (FiO2) ≥ 0.40 Anticipated or confirmed intensive care unit (ICU) admission Exclusion Criteria: Organ dysfunction present > 24 hours at time randomization Limitations of care (defined as refusal of cardiovascular and respiratory support described under inclusion criteria) including "do not intubate" (DNI) status Development of sepsis while in the hospital ( i.e not present on admission to hospital) Chronic hypoxemia requiring supplemental non-invasive oxygen or home mechanical ventilation Chronic cardiovascular failure requiring home mechanical hemodynamic support or home chemical hemodynamic support Known allergy or known contraindication to alirocumab Chronic disease/illness that, in the opinion of the site investigator, have an expected lifespan of < 30 days unrelated to current sepsis diagnosis (e.g, stage IV malignancy, neurodegenerative disease, etc.) Requirement of more than 6 liters (L) nasal cannula (NC) if not receiving invasive mechanical ventilation Pregnancy Prisoner or incarceration Current participation in another interventional pharmaceutical research study for sepsis Inability or unwillingness of subject or legal surrogate/representative to give written informed consent

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jonathan Sevransky, MD, MHS

Phone

404-686-6162

jsevran@emory.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Alex Hall, DHSc, MS

Phone

404-778-1585

alex.hall@emory.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jonathan Sevransky, MD, MHS

Organizational Affiliation

Emory University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Grady Memorial Hospital

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30303

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Alex Hall, DHSc, MS

Phone

404-778-1585

alex.hall@emory.edu

Facility Name

Emory University Hospital

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Individual Site Status

Recruiting

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Deidentified individual participant data is shared with the funding source (Regeneron) and data will be made available for sharing with other researchers upon request.

IPD Sharing Time Frame

Individual participant data will be available for sharing one year after publication of the primary manuscript from this study.

IPD Sharing Access Criteria

Researchers interested in accessing data from this study should contact the study principal investigator.

Learn more about this trial

Alirocumab in Patients With Sepsis

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