Alirocumab for Sepsis

(PALMS Trial)

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

50 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the idea that Alirocumab for Sepsis is an effective drug?

The available research does not provide any data specifically supporting the effectiveness of Alirocumab for treating sepsis. The studies mentioned focus on other treatments and approaches for sepsis, such as afelimomab, immune checkpoint inhibitors, and interleukin-1 receptor antagonists. None of these studies mention Alirocumab or provide evidence of its effectiveness for sepsis. ^{1 2 3 4 5}

What safety data is available for Alirocumab in treating sepsis?

The provided research does not contain specific safety data for Alirocumab (also known as Praluent, REGN727, SAR236553) in the treatment of sepsis. The studies mentioned focus on other treatments and challenges in sepsis therapy, such as interleukin-1 receptor antagonist, recombinant human activated protein C, and anti-TNF-alpha antibody afelimomab. Therefore, no safety data for Alirocumab in sepsis is available in the provided research. ^{1 4 5 6 7}

Is the drug Alirocumab a promising treatment for sepsis?

The provided research articles do not mention Alirocumab or its effects on sepsis. Therefore, based on the available information, we cannot determine if Alirocumab is a promising treatment for sepsis. ^{1 3 5 8 9}

Research Team

Jonathan Sevransky, MD

Principal Investigator

Emory University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2019]

2. United States 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). [2020]

3. England pubmed.ncbi.nlm.nih.gov

A neutrophil-B-cell axis impacts tissue damage control in a mouse model of intraabdominal bacterial infection via Cxcr4. [2023]

4. United States 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?*. [2021]

5. United States 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. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. Netherlands pubmed.ncbi.nlm.nih.gov

The failure of biologics in sepsis: where do we stand? [2013]

8. England pubmed.ncbi.nlm.nih.gov

TICAM2-related pathway mediates neutrophil exhaustion. [2021]

9. India pubmed.ncbi.nlm.nih.gov

Afelimomab. [2007]