Immunomodulatory Effects of Dexamethasone, Tocilizumab and Anakinra During Experimental Human Endotoxemia (DEDICATE-LPS)

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.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Endotoxemia; Dexamethasone; Neuroinflammatory Response; Tocilizumab; Anakinra; Immunosuppresion
• Intervention / Treatment: Drug: Dexamethasone; Biological: LPS; Drug: Tocilizumab; Drug: Anakinra; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Nicole Waalders, MD; Phone Number: +31243668420; Email: nicole.waalders@radboudumc.nl
• Study Contact Backup: Name: Matthijs Kox, PhD; Phone Number: +31243653881; Email: matthijs.kox@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500 HB
      • Recruiting
      • Intensive Care Medicine, Radboud University Nijmegen Medical Centre
      • Principal Investigator: Peter Pickkers, MD, PhD
      • Contact: Nicole Waalders, MD; Phone Number: +31243668420; Email: nicole.waalders@radboudumc.nl
      • Contact: Matthijs Kox, PhD; Phone Number: +31243653881; Email: matthijs.kox@radboudumc.nl
      • Sub-Investigator: Matthijs Kox, PhD
      • Sub-Investigator: Nicole Waalders, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1: dexamethasone; 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; Dexamethasone 6mg in 10mL NaCl 0.9% i.v. bolus + 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.; Other Names: Endotoxin; Lipopolysaccharide (LPS from E. coli type O113)
Active Comparator: Group 2: Tocilizumab; 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.	Biological: LPS; 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); 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.; Other Names: RoActemra; Tyenne
Active Comparator: Group 3: Anakinra; 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.	Biological: LPS; 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); 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.; Other Names: Kineret
Placebo Comparator: Group 4: Placebo; 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.	Biological: LPS; 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); Drug: Placebo; 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%
No Intervention: Group 5: Control; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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	8 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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).	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).	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.	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.	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.	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.	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.	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	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.	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).	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).	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.	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.	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).	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.	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.	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.	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.	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.	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.	8 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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).	Upon the screening day and both LPS challenges (3 days)

Collaborators and Investigators

• Sponsor: Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2024
• Primary Completion (Estimated): September 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: September 20, 2024
• First Submitted That Met QC Criteria: September 30, 2024
• First Posted (Actual): October 3, 2024

Study Record Updates

• Last Update Posted (Actual): April 4, 2025
• Last Update Submitted That Met QC Criteria: April 1, 2025
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Immunosuppression; Neuroinflammation; Systemic inflammation; Tocilizumab; Sepsis; Dexamethasone; Anakinra; Immunoparalysis; Human endotoxemia; Hyperinflammatory response
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Bacteremia; Toxemia; Endotoxemia; Antineoplastic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antirheumatic Agents; Dexamethasone; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: DEDICATE-LPS; 2023-506556-24-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Demographic data (pseudonimized); Outcome data (pseudonimized)
• IPD Sharing 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.
• IPD Sharing Access Criteria: Data will be made available upon reasonable request to the corresponding author.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes