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NCT Number: NCT06624436

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

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.

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Key information

Conditions

Sepsis Anakinra Bacteremia Dexamethasone Endotoxemia Immunosuppresion Infections Inflammation Nervous System Diseases Neuroinflammatory Diseases Neuroinflammatory Response Pathologic Processes Pathological Conditions, Signs and Symptoms Systemic Inflammatory Response Syndrome Tocilizumab Toxemia

Age range

18 year–35 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 4

Primary location

Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

Location status: Recruiting

Location contact

Matthijs Kox, PhD

CONTACT

[email protected]

+31243653881

Matthijs Kox, PhD

SUB_INVESTIGATOR

Nicole Waalders, MD

CONTACT

[email protected]

+31243668420

Nicole Waalders, MD

SUB_INVESTIGATOR

Peter Pickkers, MD, PhD

PRINCIPAL_INVESTIGATOR

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Male subjects aged ≥18 and ≤35 years
  • Body mass index (BMI) ≥18 and ≤30 kg/m2
  • Healthy (as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram and routine clinical laboratory parameters)
  • Able to comprehend and sign the Information letter and Informed Consent (IC) prior to enrolment in the study.

Exclusion criteria

  • Use of any prescription medication or over-the-counter non-steroidal anti-inflammatory drugs
  • Known anaphylaxis or hypersensitivity to any (non-)investigational products or their excipients
  • History of chronic headache or previous post-dural puncture headache (PDPH)
  • History or signs of severe atopic syndrome (asthma, rhinitis with medication and/or eczema)
  • History of any disease associated with immune deficiency
  • History of cancer in the last 5 years (excluding localised skin cancer or carcinoma in situ)
  • History or signs of haematological disease
  • History or signs of thromboembolic disorders
  • History of peptic / gastric ulcer disease
  • History of psychiatric disorders
  • Thrombocytopenia (<150*109/mL) or anaemia (<8.0 mmol/L)
  • History, signs or symptoms of cardiovascular disease, in particular:
  • Prone to vagal collapse
  • History of atrial or ventricular arrhythmia
  • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrio-ventricular block or a complete left bundle branch block
  • Hypertension (defined as RR systolic > 160 or RR diastolic > 90 mmHg)
  • Hypotension (defined as RR systolic < 100 or RR diastolic < 50 mmHg)
  • Renal impairment (defined as plasma creatinine >120 μmol/L)
  • Liver enzyme abnormalities (above 2x the upper limit of normal)
  • Signs of infection (CRP > 20 mg/L, white blood cells > 12x109/L or
  • lt; 4x109/L)
  • Clinically significant acute illness, including infections or trauma, within 1 month prior to the first LPS challenge
  • Previous (participation in a study with) endotoxin (LPS) administration
  • Participation in an experimental intervention or drug trial within 3 months prior to the first LPS challenge
  • Any vaccination or blood donation within 1 month prior to the first LPS challenge
  • Recent hospital admission or surgery with general anaesthesia within 3 months prior to the first LPS challenge
  • Use of recreational drugs within 2 weeks prior to the first LPS challenge
  • Suspected of not being able to comply with the trial protocol
  • Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study

Treatment and study plan

Dexamethasone

Drug

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

Drug

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.

Other names: RoActemra, Tyenne

Anakinra

Drug

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.

Other names: Kineret

Placebo

Drug

Bolus of 10mL NaCl 0.9% placebo + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.

Other names: NaCl 0.9%

LPS

Biological

This is a non-investigational product. It is used as challenge agent to achieve a controlled inflammatory state.

Other names: Endotoxin, Lipopolysaccharide (LPS from E. coli type O113)

Primary outcomes

  1. Between-group differences in plasma TNF concentrations upon the second LPS challenge

    Time frame: 1 day (during 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.

  2. Within and between-group differences in CSF TNF concentrations during repeated experimental human endotoxemia

    Time frame: 8 days

    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

Secondary outcomes

  1. 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).

    Time frame: 1 day (during the second LPS challenge)

    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.

  2. 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.

    Time frame: 8 days

    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.

  3. 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).

    Time frame: 1 day (during the second LPS challenge)

    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.

  4. 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

    Time frame: 8 days

    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.

  5. Between-group differences in mHLA-DR during the first and second LPS challenge.

    Time frame: 8 days

    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.

  6. 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).

    Time frame: 1 day (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 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).

  7. 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).

    Time frame: 1 day (during the first LPS challenge)

    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).

  8. Between-group differences in symptom scores during the first LPS challenge.

    Time frame: 1 day (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.

  9. Between-group differences in blood pressure during the first LPS challenge.

    Time frame: 1 day (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.

  10. Between-group differences in temperature during the first LPS challenge.

    Time frame: 1 day (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.

  11. Between-group differences in heart rate during the first LPS challenge.

    Time frame: 1 day (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.

  12. Within and between-group differences in blood leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways upon both LPS challenges.

    Time frame: 8 days

    The effects of LPS-induced inflammation, dexamethasone, tocilizumab and anakinra on transcriptome profiles of circulating leukocytes during the first and second LPS challenges.

  13. Within and between-group differences in cytokine production of leukocyte cultures

    Time frame: 8 days

    The effects of dexamethasone, tocilizumab and anakinra on ex vivo leukocytic cytokine production

  14. Within and between-group differences in plasmatic coagulation parameters (e.g. whole blood thrombin generation and plasma thrombin generation) upon both LPS challenges.

    Time frame: 8 days

    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.

  15. 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).

    Time frame: 8 days

    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).

  16. 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).

    Time frame: 8 days

    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).

  17. 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

    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.

  18. Within and between-group differences in CSF leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways upon both LPS challenges.

    Time frame: 8 days

    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.

  19. Correlation between systemic and CSF markers during systemic inflammation upon both LPS challenges (e.g. cytokines, Olink, transcriptome profiles).

    Time frame: 8 days

    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).

  20. Concentrations of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.

    Time frame: 8 days

    The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.

  21. Kel (elimination rate constant) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.

    Time frame: 8 days

    The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.

  22. Tmax (time at maximum concentration) of dexamethasone, tocilizumab and anakinra in blood and CSF upon both LPS-challenges.

    Time frame: 8 days

    The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.

  23. Cmax (maximum concentration) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.

    Time frame: 8 days

    The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.

  24. AUCs (area under the curves) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.

    Time frame: 8 days

    The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.

  25. T1/2 (terminal elimination half-life) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.

    Time frame: 8 days

    The pharmacokinetics of dexamethasone, tocilizumab and anakinra in blood and CSF during LPS-induced inflammation.

Other outcomes

  1. 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).

    Time frame: 8 days

    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.

  2. Correlation between cytokines in plasma, saliva, and tear fluid during systemic inflammation upon both LPS challenges.

    Time frame: 8 days

    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.

  3. Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in saliva upon both LPS challenges.

    Time frame: 8 days

    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.

  4. Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in tear fluid upon both LPS challenges.

    Time frame: 8 days

    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.

  5. Number of adverse events related to the use of dexamethasone, tocilizumab and anakinra.

    Time frame: 8 days

    Safety of dexamethasone, tocilizumab and anakinra as reflected by the number of adverse events related to their use.

  6. Correlation of blood nitric oxide concentrations between exercise, stress and inflammation.

    Time frame: Upon the screening day and both LPS challenges (3 days)

    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).

Study contacts

Contact information is provided by the study sponsor or research team.

Matthijs Kox, PhD

CONTACT

[email protected]

+31243653881

Nicole Waalders, MD

CONTACT

[email protected]

+31243668420

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Registry information

Acronym: DEDICATE-LPS

Important dates

Study start
2024
Primary completion
2025
Study completion
2025
First posted
Oct 3, 2024
Registry last updated
Apr 4, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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