RECRUITINGPhase 4INTERVENTIONAL

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

About This Trial

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.

Who May Be Eligible (Plain English)

Who May Qualify: - 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 willing to sign a consent form (IC) prior to enrolment in the study. Who Should NOT Join This Trial: - 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 ...See full criteria on ClinicalTrials.gov Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

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

Treatments Being Tested

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.

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.

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.

DRUG

Placebo

Bolus of 10mL NaCl 0.9% placebo + 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.

Locations (1)

Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Nijmegen, Gelderland, Netherlands