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

NCT06624436 | Recruiting Phase 4 FDA Drug

• 2 other identifiers: DEDICATE-LPS2023-506556-24-00
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Sepsis; Immunosuppression; Systemic inflammation; Neuroinflammation; Anakinra; Dexamethasone; Tocilizumab; Human endotoxemia; Immunoparalysis; Hyperinflammatory response

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (25)

• 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).

  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.

  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).

  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

  8 days

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

  8 days

Other Outcomes (6)

• 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).

  8 days

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

  8 days

Study Arms (5)

Group 1: dexamethasone

ACTIVE COMPARATOR

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

Group 2: Tocilizumab

ACTIVE COMPARATOR

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

Group 3: Anakinra

ACTIVE COMPARATOR

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

Group 4: Placebo

PLACEBO COMPARATOR

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

Group 5: Control

NO INTERVENTION

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.

Interventions

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.

Group 1: dexamethasone

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.

Also known as: RoActemra, Tyenne

Group 2: Tocilizumab

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.

Also known as: Kineret

Group 3: Anakinra

Placebo DRUG

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%

Group 4: Placebo

LPS BIOLOGICAL

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)

Group 1: dexamethasone; Group 2: Tocilizumab; Group 3: Anakinra; Group 4: Placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, 6500 HB, Netherlands

RECRUITING

MeSH Terms

Conditions

Sepsis; Endotoxemia; Neuroinflammatory Diseases

Interventions

Dexamethasone; tocilizumab; Interleukin 1 Receptor Antagonist Protein; Sodium Chloride; Endotoxins; Lipopolysaccharides

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bacteremia; Toxemia; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Bacterial Toxins; Toxins, Biological; Glycoconjugates; Carbohydrates; Polysaccharides, Bacterial; Polysaccharides; Lipids; Antigens, Bacterial; Antigens

Central Study Contacts

Nicole Waalders, MD

CONTACT

+31243668420; nicole.waalders@radboudumc.nl

Matthijs Kox, PhD

CONTACT

+31243653881; matthijs.kox@radboudumc.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: September 20, 2024
• First Posted: October 3, 2024
• Study Start: October 24, 2024
• Primary Completion: September 1, 2025
• Study Completion: December 1, 2025
• Last Updated: April 4, 2025

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: 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.

Locations

NL (1)