A Phase 4 interventional study of Dexamethasone and Tocilizumab in Sepsis, Neuroinflammatory Response and Immunosuppresion, sponsored by Radboud University Medical Center. Recruiting at 1 site in Netherlands. Open to male participants aged 18 Years to 35 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-04-04.
Sponsored by Radboud University Medical Center · Phase 4, Interventional, and Treatment
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:
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):
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.
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.
81 studies on the registry are indexed under Endotoxemia; 7 are open to participants now.
This study's planned enrollment of 52 is above the median of 31 across 70 interventional studies indexed under Endotoxemia.
Browse Endotoxemia studies →Radboud University Medical Center is the lead sponsor of 986 studies on the registry; 136 are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 0 (0%) have results posted.
Compared within Endotoxemia, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Sepsis. The counts are of registry records indexed under each term, refreshed daily. How we classify →
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
History, signs or symptoms of cardiovascular disease, in particular:
Signs of infection (CRP > 20 mg/L, white blood cells > 12x109/L or
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
This arm (n = 12) of healthy male volunteers will have two LPS challenges (day 0 and day 7) and will receive dexamethasone infusion in 1 hour on the first LPS challenge.
Drug: Dexamethasone · Biological: LPS
This arm (n = 12) of healthy male volunteers will have two LPS challenges (day 0 and day 7) and will receive Tocilizumab infusion in 1 hour on the first LPS challenge.
Drug: Tocilizumab · Biological: LPS
This arm (n = 12) of healthy male volunteers will have two LPS challenges (day 0 and day 7) and will receive Anakinra infusion in 1 hour on the first LPS challenge.
Drug: Anakinra · Biological: LPS
This arm (n = 12) of healthy male volunteers will have two LPS challenges (day 0 and day 7) and will receive a placebo infusion in 1 hour on the first LPS challenge.
Drug: Placebo · Biological: LPS
This arm (n = 4) of healthy male volunteers won't receive an LPS challenge or any of the study treatments. This group will be used to familiarise the study team with the study procedures and to establish the effect of placement of an intrathecal catheter on systemic and neuroinflammation.
Dexamethasone 6mg in 10mL NaCl 0.9% i.v. bolus + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.
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.
Also known as: RoActemra, Tyenne
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.
Also known as: Kineret
Bolus of 10mL NaCl 0.9% placebo + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.
Also known as: NaCl 0.9%
This is a non-investigational product. It is used as challenge agent to achieve a controlled inflammatory state.
Also known as: Endotoxin, Lipopolysaccharide (LPS from E. coli type O113)
Between-group differences in plasma TNF concentrations upon the second LPS challenge
The effects of dexamethasone, tocilizumab and anakinra on the development of immunoparalysis in a repeated endotoxemia model in humans, reflected by between-group differences in plasma TNF concentrations upon the second LPS challenge.
Time frame: 1 day (during second LPS challenge)
Within and between-group differences in CSF TNF concentrations during repeated experimental human endotoxemia
The extent of the neuroinflammatory response as well as the effects of dexamethasone, tocilizumab and anakinra on neuroinflammation, reflected by within and between-group differences in CSF TNF concentrations during repeated experimental human endotoxemia
Time frame: 8 days
Between-group differences in plasma cytokine concentrations during the second LPS challenge (e.g. IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40).
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as reflected by plasma concentrations of other mediators than TNF (e.g. IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40) during the second LPS challenge.
Time frame: 1 day (during the second LPS challenge)
Between-group differences in the log2-fold change of the Area Under the Curves (AUCs) of plasma cytokine concentrations (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40) during the first and second LPS challenges.
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as reflected by between-group differences in the log2-fold change of the Area Under the Curves (AUCs) of plasma concentrations of other mediators than TNF during the first and second LPS challenges.
Time frame: 8 days
Between-group differences in other plasma inflammatory proteins upon the second LPS challenge, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as measured by the Olink Target 96 inflammation panel (92 protein biomarkers) upon the second LPS challenge.
Time frame: 1 day (during the second LPS challenge)
Between-group differences in the log2-fold change of peak plasma concentrations of other inflammatory proteins, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers), during the first and second LPS challenges
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as measured by the Olink Target 96 inflammation panel (92 protein biomarkers), during the first and second LPS challenges.
Time frame: 8 days
Between-group differences in mHLA-DR during the first and second LPS challenge.
The effects of dexamethasone, tocilizumab and anakinra on the development of systemic immunoparalysis as reflected by between-group differences in mHLA-DR during the first and second LPS challenge.
Time frame: 8 days
Between-group differences in plasma cytokine concentrations during the first LPS challenge (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40).
The effects of dexamethasone, tocilizumab and anakinra on the acute systemic inflammatory response during the first LPS challenge as reflected by between-group differences in plasma cytokine concentrations (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40).
Time frame: 1 day (during the first LPS challenge)
Between-group differences in other plasma inflammatory proteins upon the first LPS challenge, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
The effects of dexamethasone, tocilizumab and anakinra on the acute systemic inflammatory response during the first LPS challenge as measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
Time frame: 1 day (during the first LPS challenge)
Between-group differences in symptom scores during the first LPS challenge.
The effects of dexamethasone, tocilizumab and anakinra on the acute systemic inflammatory response during the first LPS challenge as reflected by between-group differences in symptom scores.
Time frame: 1 day (during the first LPS challenge)
Between-group differences in blood pressure during the first LPS challenge.
The effects of dexamethasone, tocilizumab and anakinra on the acute systemic inflammatory response during the first LPS challenge as reflected by between-group differences in blood pressure.
Time frame: 1 day (during the first LPS challenge)
Between-group differences in temperature during the first LPS challenge.
The effects of dexamethasone, tocilizumab and anakinra on the acute systemic inflammatory response during the first LPS challenge as reflected by between-group differences in temperature.
Time frame: 1 day (during the first LPS challenge)
Between-group differences in heart rate during the first LPS challenge.
The effects of dexamethasone, tocilizumab and anakinra on the acute systemic inflammatory response during the first LPS challenge as reflected by between-group differences in heart rate.
Time frame: 1 day (during the first LPS challenge)
Within and between-group differences in blood leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways upon both LPS challenges.
The effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of circulating leukocytes during the first and second LPS challenges.
Time frame: 8 days
Within and between-group differences in cytokine production of leukocyte cultures
The effects of dexamethasone, tocilizumab and anakinra on ex vivo leukocytic cytokine production
Time frame: 8 days
Within and between-group differences in plasmatic coagulation parameters (e.g. whole blood thrombin generation and plasma thrombin generation) upon both LPS challenges.
The effects of dexamethasone, tocilizumab and anakinra on plasmatic coagulation, as reflected by within and between-group differences in thrombin generation during the first and second LPS challenges.
Time frame: 8 days
Within and between-group differences in CSF cytokine concentrations during both LPS challenges (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G CSF, IP-10, CX3CL1, YKL-40, HSP-70, Aß-40, Aß-42, pTau, NfL).
The effects of LPS administration as well as dexamethasone, tocilizumab and anakinra on neuroinflammation during the first and second LPS challenges as reflected by within and between-group differences in CSF cytokine concentrations (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G CSF, IP-10, CX3CL1, YKL-40, HSP-70, Aß-40, Aß-42, pTau, NfL).
Time frame: 8 days
Within and between-group differences in other inflammatory proteins in CSF upon both LPS challenges, measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
The effects of LPS administration as well as dexamethasone, tocilizumab and anakinra on neuroinflammation during the first and second LPS challenges, as reflected by within and between-group differences in other inflammatory proteins in CSF, measured by the Olink Target 96 inflammation panel (92 protein biomarkers).
Time frame: 8 days
Between-group differences in the log2-fold change of the AUCs of CSF cytokine concentrations during the first and second LPS challenges.
The effects of LPS administration as well as dexamethasone, tocilizumab and anakinra on neuroinflammation during the first and second LPS challenges as reflected by within and between-group differences in the log2-fold change of the AUCs of CSF cytokine concentrations during the first and second LPS challenges.
Time frame: 8 days
Within and between-group differences in CSF leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways upon both LPS challenges.
The effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of cells in the CSF during the first en second LPS challenges.
Time frame: 8 days
Correlation between systemic and CSF markers during systemic inflammation upon both LPS challenges (e.g. cytokines, Olink, transcriptome profiles).
The relationship between systemic inflammatory responses and neuroinflammation as reflected by the correlation between systemic and CSF markers during systemic inflammation during the first en second LPS challenges (e.g. cytokines, Olink, transcriptome profiles).
Time frame: 8 days
Concentrations of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.
Time frame: 8 days
Kel (elimination rate constant) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.
Time frame: 8 days
Tmax (time at maximum concentration) of dexamethasone, tocilizumab and anakinra in blood and CSF upon both LPS-challenges.
The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.
Time frame: 8 days
Cmax (maximum concentration) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.
Time frame: 8 days
AUCs (area under the curves) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.
Time frame: 8 days
T1/2 (terminal elimination half-life) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.
Time frame: 8 days
Within and between-group differences in cytokine concentrations in saliva and tear fluid during both LPS challenges (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10).
The effects of LPS administration as well as dexamethasone, tocilizumab and anakinra on salivary and tear fluid cytokine levels, as reflected by within and between-group differences in cytokine concentrations (e.g. TNF, IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10) during the first and second LPS challenges.
Time frame: 8 days
Correlation between cytokines in plasma, saliva, and tear fluid during systemic inflammation upon both LPS challenges.
The relationship between systemic, salivary and tear fluid cytokine responses as reflected by the correlation between cytokines in plasma, saliva, and tear fluid during systemic inflammation during the first and second LPS challenges.
Time frame: 8 days
Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in saliva upon both LPS challenges.
The effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of cells in saliva, as reflected by within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells during the first and the second LPS challenges.
Time frame: 8 days
Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in tear fluid upon both LPS challenges.
The effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of cells in tear fluid, as reflected by within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells during the first and the second LPS challenges.
Time frame: 8 days
Number of adverse events related to the use of dexamethasone, tocilizumab and anakinra.
Safety of dexamethasone, tocilizumab and anakinra as reflected by the number of adverse events related to their use.
Time frame: 8 days
Correlation of blood nitric oxide concentrations between exercise, stress and inflammation.
The kinetics of blood nitric oxide concentrations during exercise (bicycling on a home-trainer during screening), stress and systemic inflammation (during the first and second LPS challenges).
Time frame: Upon the screening day and both LPS challenges (3 days)
Plan to share: Yes — Demographic data (pseudonimized) Outcome data (pseudonimized)
Supporting information: Study protocol, Analytic code
Time frame: Beginning directly after publication of the paper describing the main results of the study and ending 30 years after publication of the paper describing the main results.
Access criteria: Data will be made available upon reasonable request to the corresponding author.
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Studies of the drugs tested here: Dexamethasone · Tocilizumab · Interleukin 1 Receptor Antagonist Protein
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