Alirocumab for Sepsis

(PALMS Trial)

No longer recruiting at 1 trial location

Overseen By Alex Hall, DHSc, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jonathan Sevransky

Disqualifiers: Chronic hypoxemia, Chronic cardiovascular failure, Pregnancy, others

Compensation: Varies

Number of Visits: 1

Duration: 30 minutes

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether alirocumab, a drug that may lower cholesterol, can reduce inflammation from severe infections causing low blood pressure or breathing problems. Participants will receive either an IV dose of alirocumab or a placebo (a harmless substance with no effect). Ideal candidates have a confirmed or suspected infection causing serious heart or lung issues, such as the need for mechanical breathing support or medications to maintain blood pressure. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking treatment.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the trial involves patients with sepsis who are likely on critical medications, it is unlikely that you will need to stop them. Please consult with the trial coordinators for specific guidance.

Is there any evidence suggesting that alirocumab is likely to be safe for humans?

Research shows that alirocumab, a drug typically used to lower cholesterol, seems safe for patients with severe sepsis and septic shock. Studies have found that it does not cause harmful effects in these cases. While more information about its safety is still being gathered, earlier findings suggest that alirocumab is generally well-tolerated. Evidence also indicates that using PCSK9 inhibitors, like alirocumab, in people with high heart disease risk does not increase the risk of infections. This provides some confidence about its safety in very sick patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for sepsis, which typically involve antibiotics and supportive care like fluids and oxygen therapy, alirocumab works differently by targeting the body's immune response. Alirocumab is a monoclonal antibody that inhibits PCSK9, a protein involved in cholesterol regulation, which may help reduce inflammation and improve outcomes in sepsis patients. Researchers are excited about alirocumab because it offers a novel approach to managing sepsis, potentially improving survival rates for critically ill patients by addressing the underlying immune dysfunction rather than just treating the symptoms.

What evidence suggests that alirocumab might be an effective treatment for sepsis?

Research has shown that alirocumab, a cholesterol-lowering drug, might also reduce inflammation in people with sepsis. In this trial, some participants will receive alirocumab to assess its safety and effectiveness in treating severe sepsis and septic shock. One study found that alirocumab was safe for patients with these conditions, showing promising results. Although another study did not find a clear connection between using drugs like alirocumab and sepsis, the drug has effectively lowered bad cholesterol in other conditions. This ability to reduce inflammation could be useful in treating sepsis, a condition with high mortality rates. ^{1 3 4 6 7}

Who Is on the Research Team?

Jonathan Sevransky, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for adults with sepsis, showing signs like low blood pressure or breathing trouble due to infection. They must be receiving antimicrobials and have either cardiovascular dysfunction needing vasopressors or respiratory failure requiring support. Excluded are those with chronic conditions affecting survival, current participation in another sepsis drug study, known alirocumab allergy, pregnancy, or incarceration.

Inclusion Criteria

I have severe lung or heart problems due to a serious infection.

I am expected to be or have been admitted to the ICU.

I am being treated for an infection with antibiotics and have had blood tests to confirm it.

Exclusion Criteria

Known allergy or known contraindication to alirocumab

I have had organ dysfunction for more than 24 hours.

Prisoner or incarceration

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single IV infusion of alirocumab or placebo

30 minutes

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

180 days

What Are the Treatments Tested in This Trial?

Interventions

• Alirocumab
• Placebo

Trial Overview The trial tests if alirocumab can reduce inflammation in sepsis patients. Participants will randomly receive one IV infusion of either alirocumab or a placebo to see if it helps manage their condition better than standard treatment alone.

How Is the Trial Designed?

Group I: Alirocumab Experimental Treatment 1 Intervention

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

Group II: Placebo Placebo Group 1 Intervention

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

Alirocumab is already approved in European Union, United States for the following indications:

Approved in European Union as Praluent for:

• High cholesterol - Familial Homozygous
• Cardiovascular Risk Reduction
• High cholesterol - Familial Heterozygous
• High Cholesterol

Approved in United States as Praluent for:

• High cholesterol - Familial Homozygous
• Cardiovascular Risk Reduction
• High cholesterol - Familial Heterozygous
• Primary hyperlipidemia

Who Is Running the Clinical Trial?

Jonathan Sevransky

Lead Sponsor

Trials

1

Recruited

50+

Regeneron Pharmaceuticals

Industry Sponsor

Trials

690

Recruited

948,000+

Founded

1988

Headquarters

Tarrytown, USA

Known For

Precision medicine

Top Products

Dupixent, EYLEA, Libtayo, Praluent

Leonard Schleifer

Regeneron Pharmaceuticals

Chief Executive Officer since 1988

MD and PhD in Medicine

George Yancopoulos

Regeneron Pharmaceuticals

Chief Medical Officer since 1997

MD from Harvard Medical School

Published Research Related to This Trial

Afelimomab, an anti-TNF-alpha therapy, has shown promise in being well tolerated and potentially beneficial for certain patients with sepsis, based on clinical trials.

A large randomized clinical trial has been completed to further evaluate afelimomab's efficacy in severe sepsis, with results pending, highlighting the need for better patient selection for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Afelimomab. Vincent, JL.[2007]

Afelimomab, an antibody fragment targeting TNF-alpha, was found to be safe and well tolerated in a phase I/II trial involving 48 sepsis patients, with predictable pharmacokinetics and no significant adverse effects related to the drug.

While afelimomab did not significantly impact 28-day mortality rates, it did lead to increased TNF levels and decreased interleukin-6 levels, suggesting a potential mechanism of action in modulating inflammatory responses in sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter, open-label, prospective, randomized, dose-ranging pharmacokinetic study of the anti-TNF-alpha antibody afelimomab in patients with sepsis syndrome. Gallagher, J., Fisher, C., Sherman, B., et al.[2019]

In a phase II clinical trial involving 99 patients with sepsis syndrome, human recombinant interleukin-1 receptor antagonist (IL-1ra) demonstrated a dose-dependent survival benefit, with mortality rates decreasing from 44% in the placebo group to 16% in the highest dose group (133 mg/hr).

IL-1ra was well tolerated and showed a significant reduction in the APACHE II score, indicating improved clinical status, suggesting it may be a safe and effective treatment option for sepsis, particularly in patients with high interleukin-6 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. Fisher, CJ., Slotman, GJ., Opal, SM., et al.[2019]

In a mouse model of severe sepsis, B cells and neutrophils were identified as crucial regulators that help maintain tissue integrity and reduce organ damage despite high levels of infection.

Administering a Cxcr4 agonist improved tissue damage control and prevented liver damage during sepsis, suggesting that targeting neutrophil Cxcr4 activation could be a promising therapeutic strategy for enhancing disease tolerance in sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A neutrophil-B-cell axis impacts tissue damage control in a mouse model of intraabdominal bacterial infection via Cxcr4. Gawish, R., Maier, B., Obermayer, G., et al.[2023]

Prolonged stimulation with lipopolysaccharides (LPS) in murine neutrophils leads to an exhausted phenotype similar to that seen in human sepsis, characterized by increased expression of inflammatory markers and immune suppressors.

The study identifies TICAM2 as a crucial mediator of neutrophil exhaustion, suggesting that targeting TICAM2 could be a promising strategy for treating severe systemic inflammation and preventing multi-organ injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TICAM2-related pathway mediates neutrophil exhaustion. Lin, R., Zhang, Y., Pradhan, K., et al.[2021]

The review highlights several promising immunomodulatory strategies for treating sepsis, including intravenous clarithromycin, PMX-B haemoperfusion, recombinant thrombomodulin, and IgM/IgA enriched immunoglobulin preparations, suggesting potential efficacy in specific sepsis scenarios.

A personalized treatment approach is essential due to the diverse nature of sepsis, with recommendations for tailored interventions based on the type of sepsis, such as using clarithromycin for ventilator-associated pneumonia and PMX-B for abdominal severe sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The failure of biologics in sepsis: where do we stand? Giamarellos-Bourboulis, EJ.[2013]

BMS-936559, an immune checkpoint inhibitor, was found to be well tolerated in a study of 24 participants with sepsis, showing no drug-related serious adverse events and no evidence of harmful cytokine storms.

At higher doses, BMS-936559 appeared to enhance immune function by increasing monocyte human leukocyte antigen-DR expression, suggesting potential benefits in restoring immune status in sepsis patients over a 28-day period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559). Hotchkiss, RS., Colston, E., Yende, S., et al.[2020]

The development of new therapies for sepsis has significantly slowed, with no immunomodulating treatments showing consistent benefits in clinical trials, highlighting the need for a reevaluation of current research approaches.

The review suggests 12 recommendations to enhance future sepsis studies, including defining better molecular targets, using realistic sample sizes, and considering biomarker-driven studies to identify patients who would benefit most from new treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*. Opal, SM., Dellinger, RP., Vincent, JL., et al.[2021]

Despite significant efforts in developing new immunomodulatory agents for treating shock and sepsis, many have failed in clinical trials due to preclinical models that do not accurately reflect real clinical conditions.

This review highlights the need for better preclinical models that align with clinical realities to improve the development of safe and effective treatments for these life-threatening conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Animal models of sepsis and shock: a review and lessons learned. Deitch, EA.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05469347

NCT05469347 | Alirocumab in Patients with Sepsis 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11586949/

Proprotein Convertase Subtilisin Kexin 9 Inhibitor in Severe ... Conclusions: Alirocumab appears safe in severe sepsis and septic shock patients. The outcome data are promising. Only a basic safety profile can be assessed ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0002934323001444

The Association Between PCSK9 Inhibitor Use and Sepsis This study found neither beneficial nor harmful association among PCSK9 inhibitors, sepsis, and severe infections in populations with high cardiovascular risk.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8820199/

Evaluation of the Effectiveness and Safety of Alirocumab ... Alirocumab use in 24 statin-intolerant veterans resulted in a significant reduction in LDL-C at 4 and 24 weeks after initiation.

5. clinicaltrial.be clinicaltrial.be/fr/details/15895?per_page=100&only_recruiting=0&only_eligible=0&only_active=0

Alirocumab in Patients with Sepsis - Découvrir facilement... Though outcomes have improved with the bundled deployment of these strategies, mortality remains high at 20 - 30%. Despite over a hundred phase ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39584843/

Proprotein Convertase Subtilisin Kexin 9 Inhibitor in ... Conclusions: Alirocumab appears safe in severe sepsis and septic shock patients. The outcome data are promising. Only a basic safety profile ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01288443

Study Details | NCT01288443 | Efficacy and Safety ... To evaluate the safety and tolerability of alirocumab; To evaluate the development of anti-alirocumab antibodies; To evaluate the pharmacokinetics of alirocumab.