Alirocumab in Patients With Sepsis

Sepsis Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05469347
• Other study ID #: STUDY00004119
• Status: Recruiting
• Phase: Phase 1
• Start date: January 4, 2023
• Est. completion date: May 2024

Study information

• Verified date: November 2023
• Source: Emory University
• Contact: Jonathan Sevransky, MD, MHS
• Phone: 404-686-6162
• Email: jsevran[@]emory.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: May 2024
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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

Related Conditions & MeSH terms

• Sepsis
• Toxemia

Intervention

Drug:
• Alirocumab
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.
• Placebo
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.

Locations

Country	Name	City	State
United States	Emory University Hospital	Atlanta	Georgia
United States	Grady Memorial Hospital	Atlanta	Georgia

Sponsors (2)

Lead Sponsor	Collaborator
Jonathan Sevransky	Regeneron Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Bacterial endotoxin level	Levels of bacterial endotoxin will be compared between study arms.	Hour 120
Primary	Lipoteichoic acid level	Levels of lipoteichoic acid will be compared between study arms.	Hour 120
Secondary	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.	Up to Day 30
Secondary	Mortality	The number of participants who die will be compared between study arms.	Up to Day 30
Secondary	ICU Mortality	The number of participants who die while in the ICU will be compared between study arms.	Up to Day 30
Secondary	Days in ICU	Length of stay in the ICU (measured in days) will be compared between study arms.	Up to Day 30
Secondary	Days in Hospital	Length of stay in the hospital (measured in days) will be compared between study arms.	Up to Day 30
Secondary	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.	Hour 120
Secondary	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.	Hour 120
Secondary	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.	Hour 120
Secondary	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.	Hour 120