NCT06624436

Immunomodulatory Effects of Dexamethasone, Tocilizumab and Anakinra During Experimental Human Endotoxemia

• Status: Recruiting
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 52 (estimated)
• Sponsor: Radboud University Medical Center · Academic / Other
• Sex: Male
• Age: 18 Years – 35 Years
• Healthy volunteers: Accepted

Summary

The goal of this clinical trial is to investigate the immunomodulatory effects of the drugs dexamethasone, tocilizumab and anakinra in healthy male subjects aged 18 to 35 undergoing experimental endotoxemia. The main questions it aims to answer are: * What are the effects of these drugs on the development of immunoparalysis in a repeated human endotoxemia model? * What is the extent of the neuroinflammatory response and how do these drugs affect neuroinflammation in a repeated human endotoxemia model? Researchers will compare these drugs to a placebo (a look-alike substance that contains no drug). Participants will visit the Intensive Care research department on two or five occasions (screening included): * The intervention group will receive an LPS challenge twice, with a week in between. Before the first LPS challenge, one of the described drugs will be administered. Blood, saliva and tear fluid will be collected regularly during the LPS challenge. Cerebrospinal fluid will also be collected through a catheter in the spinal cord. * The control group will not receive an LPS challenge or drug administration and will have only one study day. During this day, blood, saliva, tear fluid and cerebrospinal fluid will be collected as regularly as during the LPS challenge of the intervention group. During an LPS challenge, the investigators mimic blood poisoning by giving an endotoxin, also called LPS. This is a small part of the cell wall of a bacteria. This will cause transient flu-like symptoms for 3-4 hours.

Detailed description

The experimental human endotoxemia model is a controlled, standardized and safe model of systemic (sepsis-like) inflammation induced by bacterial lipopolysaccharide (LPS) in healthy volunteers. This model captures many hallmarks of both the hyperinflammatory phenotype (observed following a first LPS challenge) and the immunoparalytic phenotype (observed following a second LPS challenge one week later) of sepsis. In this study the investigators aim to determine the effects of dexamethasone, tocilizumab and anakinra within the repeated experimental human endotoxemia model on the development of immunoparalysis, reflected by between-group differences in plasma TNF (and other cytokine) concentrations upon the second LPS challenge. The investigators will also profile inflammatory parameters in cerebrospinal fluid (CSF), reflected by within- and between-group differences in CSF TNF (and other cytokine) concentrations following the first LPS challenge, to gain insights in inflammatory responses of the central nervous system. Anti-inflammatory drugs may help reduce sepsis-induced immunoparalysis and, somewhat counterintuitively, improve immune responses later by dampening the initial hyperinflammation. Pro-inflammatory cytokines, such as TNF, are key in triggering this immunosuppression. Reducing early hyperinflammation could also prevent postoperative immune suppression, lowering the risk of infections. Drugs like dexamethasone, tocilizumab, and anakinra may affect neuroinflammation, depending on their ability to cross the blood-brain barrier (BBB). Furthermore, the investigators will explore whether cytokine profiles in saliva and tear fluid can be used as a proxy for circulating cytokine responses. Saliva and tear fluid cytokines may serve as non-invasive alternatives to blood measurements, especially for vulnerable populations, though more research is needed to validate their reliability. Comprehensive assessment of cellular components and cytokine dynamics in blood, CSF, saliva, and tear fluid will be conducted using RNA sequencing, providing insights into cellular and molecular mechanisms during endotoxemia and drug effects. This research will help identify new drug targets and better understand the immunomodulatory effects of dexamethasone, tocilizumab, and anakinra on inflammation and immunosuppression.

Conditions

• Sepsis
• Neuroinflammatory Response
• Immunosuppresion
• Endotoxemia
• Anakinra
• Dexamethasone
• Tocilizumab

Interventions

Type	Name	Description
DRUG	Dexamethasone	Dexamethasone 6mg in 10mL NaCl 0.9% i.v. bolus + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.
DRUG	Tocilizumab	Tocilizumab 600mg in 100mL NaCl 0.9% i.v. in 1 hour + a bolus of 10mL NaCl 0.9% placebo infusion on the first LPS challenge.
DRUG	Anakinra	Anakinra 200mg in 100mL NaCl 0.9% i.v. in 1 hour + a bolus of 10mL NaCl 0.9% placebo infusion on the first LPS challenge.
DRUG	Placebo	Bolus of 10mL NaCl 0.9% placebo + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.
BIOLOGICAL	LPS	This is a non-investigational product. It is used as challenge agent to achieve a controlled inflammatory state.

Timeline

• Start date: 2024-10-24
• Primary completion: 2025-09-01
• Completion: 2025-12-01
• First posted: 2024-10-03
• Last updated: 2025-04-04

Locations

1 site across 1 country: Netherlands

Regulatory

• FDA-regulated drug study