SepsisPhase 4DEDICATE-LPSNCT06624436
Immunomodulatory Effects of Dexamethasone, Tocilizumab and Anakinra During Experimental Human Endotoxemia
A Phase 4 study testing Dexamethasone, Tocilizumab and Anakinra in people with Sepsis and Neuroinflammatory Response, run by Radboud University Medical Center at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Sepsis, Neuroinflammatory Response, Immunosuppresion
- What is being tested?
- Dexamethasone, Tocilizumab and Anakinra
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 52 participants
- Where
- 1 siteNetherlands
- Study dates
- 24 Oct 2024to Dec 2025
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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.
Who cannot join
- 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)
Show all 29Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, 6500 HB
Nicole Waalders, MD, +31243668420, nicole.waalders@radboudumc.nl
Matthijs Kox, PhD, +31243653881, matthijs.kox@radboudumc.nl
About this study
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?
Read more
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.
Read the 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.
- Conditions
- Sepsis, Neuroinflammatory Response, Immunosuppresion, Endotoxemia, Anakinra, Dexamethasone
- Being tested
- Dexamethasone, Tocilizumab, Anakinra, Placebo, LPS
- Keywords
- Sepsis, Immunosuppression, Systemic inflammation, Neuroinflammation, Anakinra, Dexamethasone, Tocilizumab, Human endotoxemia, Immunoparalysis, Hyperinflammatory response
- Medical subject headings
- Sepsis, Endotoxemia, Neuroinflammatory Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DexamethasoneDrug
Dexamethasone 6mg in 10mL NaCl 0.9% i.v. bolus + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.
TocilizumabDrug
Also called RoActemra, Tyenne
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.
AnakinraDrug
Also called Kineret
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.
PlaceboDrug
Also called NaCl 0.9%
Bolus of 10mL NaCl 0.9% placebo + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge.
LPSBiological
Also called Endotoxin, Lipopolysaccharide (LPS from E. coli type O113)
This is a non-investigational product. It is used as challenge agent to achieve a controlled inflammatory state.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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).
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 8 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2024
- Study start24 Oct 2024
- Primary completionSep 2025 (estimated)
- Study completionDec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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).
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 52 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06624436
- Sponsor's protocol ID
- DEDICATE-LPS
- Other IDs
- 2023-506556-24-00, 2023
- Acronym
- DEDICATE-LPS
- Status last verified
- Sep 2024
- First submitted
- 20 Sep 2024
- Last updated
- 4 Apr 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: * Demographic data (pseudonimized) * Outcome data (pseudonimized)
Study at a glance
From the registry record, last updated by the sponsor on 4 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Immunomodulatory Effects of Dexamethasone, Tocilizumab and Anakinra During Experimental Human Endotoxemia
- ClinicalTrials.gov ID
- NCT06624436
- Acronym / sponsor ID
- DEDICATE-LPS / DEDICATE-LPS
- Conditions
- Sepsis, Neuroinflammatory Response, Immunosuppresion, Endotoxemia, Anakinra, Dexamethasone
- Keywords
- Sepsis, Immunosuppression, Systemic inflammation, Neuroinflammation, Anakinra, Dexamethasone, Tocilizumab, Human endotoxemia
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 52 participants (estimated)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- 24 Oct 2024 (actual)
- Primary completion
- Sep 2025 (estimated)
- Study completion
- Dec 2025 (estimated)
- First posted
- 3 Oct 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
- 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).
| Arm | Type | Receives |
|---|---|---|
| Group 1: dexamethasone | Active comparator | Drug: Dexamethasone, Biological: LPSThis 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. |
| Group 2: Tocilizumab | Active comparator | Drug: Tocilizumab, Biological: LPSThis 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. |
| Group 3: Anakinra | Active comparator | Drug: Anakinra, Biological: LPSThis 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. |
| Group 4: Placebo | Placebo comparator | Drug: Placebo, Biological: LPSThis 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. |
| 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. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (29 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DexamethasoneDexamethasone 6mg in 10mL NaCl 0.9% i.v. bolus + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge. | Drug | Group 1: dexamethasone |
| TocilizumabAlso: RoActemra, TyenneTocilizumab 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. | Drug | Group 2: Tocilizumab |
| AnakinraAlso: KineretAnakinra 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. | Drug | Group 3: Anakinra |
| PlaceboAlso: NaCl 0.9%Bolus of 10mL NaCl 0.9% placebo + 100mL NaCl 0.9% placebo infusion in 1 hour on the first LPS challenge. | Drug | Group 4: Placebo |
| LPSAlso: Endotoxin, Lipopolysaccharide (LPS from E. coli type O113)This is a non-investigational product. It is used as challenge agent to achieve a controlled inflammatory state. | Biological | Group 1: dexamethasone, Group 2: Tocilizumab, Group 3: Anakinra, Group 4: Placebo |
Primary outcome
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.
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
25 secondary outcomes
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)
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
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)
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
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).
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).
Time frame: 1 day (during the first LPS challenge)
Between-group differences in symptom scores during the first LPS challenge.
Time frame: 1 day (during the first LPS challenge)
Between-group differences in blood pressure during the first LPS challenge.
Time frame: 1 day (during the first LPS challenge)
Between-group differences in temperature during the first LPS challenge.
Time frame: 1 day (during the first LPS challenge)
Between-group differences in heart rate during the first LPS challenge.
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.
Time frame: 8 days
Within and between-group differences in cytokine production of leukocyte cultures
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.
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).
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).
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.
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.
Time frame: 8 days
Correlation between systemic and CSF markers during systemic inflammation upon both 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.
Time frame: 8 days
Kel (elimination rate constant) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
Time frame: 8 days
Tmax (time at maximum concentration) of dexamethasone, tocilizumab and anakinra in blood and CSF upon both LPS-challenges.
Time frame: 8 days
Cmax (maximum concentration) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
Time frame: 8 days
AUCs (area under the curves) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
Time frame: 8 days
T1/2 (terminal elimination half-life) of dexamethasone, anakinra and tocilizumab in blood and CSF upon both LPS challenges.
Time frame: 8 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Apr 2025.
- Individual participant dataSharing planned: Yes. * Demographic data (pseudonimized) * Outcome data (pseudonimized)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Dexamethasone, Tocilizumab and Anakinra in people with Sepsis and Neuroinflammatory Response, run by Radboud University Medical Center at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 4 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Nicole Waalders, MD (+31243668420, nicole.waalders@radboudumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Between-group differences in plasma TNF concentrations upon the second LPS challenge (time frame: 1 day (during second LPS challenge)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Apr 2025.