Clinical trial NCT06624436: Immunomodulatory Effects of Dexamethasone, Tocilizumab and Anakinra During Experimental Human Endotoxemia
Official title: Immunomodulatory Effects of Dexamethasone, Tocilizumab and Anakinra During Experimental Human Endotoxemia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Sepsis
Neuroinflammatory Response
Immunosuppresion
Endotoxemia
Anakinra
Dexamethasone
Tocilizumab
Keywords: Sepsis
Immunosuppression
Systemic inflammation
Neuroinflammation
Anakinra
Dexamethasone
Tocilizumab
Human endotoxemia
Immunoparalysis
Hyperinflammatory response
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2024-10-03
Enrollment: 52
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: DEDICATE-LPS is a randomized double-blind placebo-controlled (double-dummy) study. A total of 48 healthy male volunteers will undergo experimental human endotoxemia twice separated by one week. Volunteers will be randomized to an allocated study treatment (dexamethasone 6 mg i.v. (n = 12), tocilizumab 600 mg i.v. (n = 12), anakinra 200 mg i.v. (n = 12) or placebo (NaCl 0.9% i.v., n = 12)). Furthermore, 4 healthy male volunteers will be enrolled as a control group (receiving no study treatment or LPS).
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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 (\&lt;150\*109/mL) or anaemia (\&lt;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 \&gt; 160 or RR diastolic \&gt; 90 mmHg)
  * Hypotension (defined as RR systolic \&lt; 100 or RR diastolic \&lt; 50 mmHg)
* Renal impairment (defined as plasma creatinine \&gt;120 μmol/L)
* Liver enzyme abnormalities (above 2x the upper limit of normal)
* Signs of infection (CRP \&gt; 20 mg/L, white blood cells \&gt; 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

Primary outcomes:
measure: Between-group differences in plasma TNF concentrations upon the second LPS challenge
timeFrame: 1 day (during second LPS challenge)
measure: Within and between-group differences in CSF TNF concentrations during repeated experimental human endotoxemia
timeFrame: 8 days
Secondary outcomes:
measure: 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).
timeFrame: 1 day (during the second LPS challenge)
measure: 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.
timeFrame: 8 days
measure: 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).
timeFrame: 1 day (during the second LPS challenge)
measure: 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
timeFrame: 8 days
measure: Between-group differences in mHLA-DR during the first and second LPS challenge.
timeFrame: 8 days
measure: 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).
timeFrame: 1 day (during the first LPS challenge)
measure: 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).
timeFrame: 1 day (during the first LPS challenge)
measure: Between-group differences in symptom scores during the first LPS challenge.
timeFrame: 1 day (during the first LPS challenge)
measure: Between-group differences in blood pressure during the first LPS challenge.
timeFrame: 1 day (during the first LPS challenge)
measure: Between-group differences in temperature during the first LPS challenge.
timeFrame: 1 day (during the first LPS challenge)
measure: Between-group differences in heart rate during the first LPS challenge.
timeFrame: 1 day (during the first LPS challenge)
measure: Within and between-group differences in blood leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways upon both LPS challenges.
timeFrame: 8 days
measure: Within and between-group differences in cytokine production of leukocyte cultures
timeFrame: 8 days
measure: Within and between-group differences in plasmatic coagulation parameters (e.g. whole blood thrombin generation and plasma thrombin generation) upon both LPS challenges.
timeFrame: 8 days
measure: 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).
timeFrame: 8 days
measure: 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).
timeFrame: 8 days
measure: Between-group differences in the log2-fold change of the AUCs of CSF cytokine concentrations during the first and second LPS challenges.
timeFrame: 8 days
measure: Within and between-group differences in CSF leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways upon both LPS challenges.
timeFrame: 8 days
measure: Correlation between systemic and CSF markers during systemic inflammation upon both LPS challenges (e.g. cytokines, Olink, transcriptome profiles).
timeFrame: 8 days
measure: Concentrations of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
timeFrame: 8 days
measure: Kel (elimination rate constant) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
timeFrame: 8 days
measure: Tmax (time at maximum concentration) of dexamethasone, tocilizumab and anakinra in blood and CSF upon both LPS-challenges.
timeFrame: 8 days
measure: Cmax (maximum concentration) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
timeFrame: 8 days
measure: AUCs (area under the curves) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
timeFrame: 8 days
measure: T1/2 (terminal elimination half-life) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
timeFrame: 8 days
Other outcomes:
measure: 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).
timeFrame: 8 days
measure: Correlation between cytokines in plasma, saliva, and tear fluid during systemic inflammation upon both LPS challenges.
timeFrame: 8 days
measure: Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in saliva upon both LPS challenges.
timeFrame: 8 days
measure: Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in tear fluid upon both LPS challenges.
timeFrame: 8 days
measure: Number of adverse events related to the use of dexamethasone, tocilizumab and anakinra.
timeFrame: 8 days
measure: Correlation of blood nitric oxide concentrations between exercise, stress and inflammation.
timeFrame: Upon the screening day and both LPS challenges (3 days)
Locations:
city: Nijmegen
country: Netherlands
facility: Intensive Care Medicine, Radboud University Nijmegen Medical Centre
state: Gelderland
Study officials:
References: