Dexamethasone for Endotoxemia-induced systemic inflammatory response

Inclusion criteria

• {"criterion_text":"- Male subjects aged ≥18 and ≤35 years\n- Body mass index (BMI) ≥18 and ≤30 kg/m2\n- Healthy (as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram and routine clinical laboratory parameters)\n- Able to comprehend and sign the Information letter and Informed Consent (IC) prior to enrolment in the study."}

Exclusion criteria

• {"criterion_text":"- Use of any prescription medication or over-the-counter non-steroidal anti-inflammatory drugs\n- Participation in an experimental intervention or drug trial within 3 months prior to the first LPS challenge\n- Any vaccination or blood donation within 1 month prior to the first LPS challenge\n- Known anaphylaxis or hypersensitivity to any (non-)investigational products or their excipients\n- Recent hospital admission or surgery with general anaesthesia within 3 months prior to the first LPS challenge\n- Use of recreational drugs within 2 weeks prior to the first LPS challenge\n- Suspected of not being able to comply with the trial protocol\n- Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study\n- History or signs of severe atopic syndrome (asthma, rhinitis with medication and/or eczema)\n- History of any disease associated with immune deficiency\n- History of cancer in the last 5 years (excluding localised skin cancer or carcinoma in situ)\n- History of psychiatric disorders\n- History or signs of haematological disease\n- History or signs of thromboembolic disorders\n- History of peptic / gastric ulcer disease\n- Thrombocytopenia (<150*109/mL) or anaemia (<8.0 mmol/L)\n- 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))\n- Renal impairment (defined as plasma creatinine >120 μmol/L)\n- Liver enzyme abnormalities (above 2x the upper limit of normal)\n- Signs of infection (CRP > 20 mg/L, white blood cells > 12x109/L or < 4x109/L)\n- Clinically significant acute illness, including infections or trauma, within 1 month prior to the first LPS challenge\n- Previous (participation in a study with) endotoxin (LPS) administration"}

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Measured as between-group differences in plasma TNF concentrations upon the second LPS challenge (plasma TNF assays comparing treatment groups)."}

Secondary endpoints

• {"endpoint_text":"- 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).\n- 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.\n- 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).\n- 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.\n- Between-group differences in mHLA-DR during the first and second LPS challenge.\n- 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).\n- 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).\n- Between-group differences in blood pressure, heart rate, temperature and symptom scores during the first LPS challenge.\n- Within and between-group differences in blood leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways upon both LPS challenges.\n- Within and between-group differences in cytokine production of whole blood cultures.\n- Within and between-group differences in plasmatic coagulation parameters.\n- Pharmacokinetic measurements (concentrations, Cmax, Tmax, AUCs, Kel and t1/2) of dexamethasone, anakinra and tocilizumab in blood upon both LPS challenges.\n- Within and between-group differences in cytokine concentrations in saliva 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).\n- Correlation between cytokines in plasma and saliva during systemic inflammation upon both LPS challenges.\n- Within and between-group differences in single cell and/or bulk mRNA profiles/transcriptomic pathways of cells in saliva upon both LPS challenges.\n- Correlation of blood nitric oxide concentrations between exercise, stress and systemic inflammation.\n- Number of adverse events related to the use of dexamethasone, tocilizumab and anakinra.\n- Within and -between-group differences in DNA methylation profiles after 3, 6 and 12 months.\n- Within and -between-group differences in plasma cytokine concentrations (e.g. IL1RA, IL-6, IL-8, IL-10, MIP-1α, MIP-1ß, MCP-1, G-CSF, IP-10, CX3CL1, YKL-40) after 3, 6 and 12 months.\n- Within and -between -group differences in other plasma inflammatory proteins after 3, 6 and 12 months, as measured by the Olink Target 96 inflammation panel (92 protein biomarkers).\n- Within and between-group differences in blood leukocyte single cell and/or bulk mRNA profiles/transcriptomic pathways after 3, 6 and 12 months.\n- Within and between-group differences in cytokine production of whole blood cultures after 3, 6 and 12 months.","definition_or_measurement_approach":"Secondary endpoints measured by plasma cytokine assays (e.g. TNF, IL-6, IL-8, IL-10, IL1RA, etc.), calculation of AUCs and log2-fold changes, Olink Target 96 inflammation panel for proteomics (92 biomarkers), mHLA-DR assays, single-cell and bulk RNA-sequencing/transcriptomics of blood and saliva cells, whole blood culture cytokine assays, standard vital sign measurements and symptom scores, coagulation parameter assays, pharmacokinetic sampling (Cmax, Tmax, AUC, Kel, t1/2), nitric oxide blood measurements, adverse event reporting, and DNA methylation profiling at 3, 6 and 12 months."}

Methods

• Recruitment materials: poster and flyer (documents: K2_Recruitment material poster_redacted; K2_Recruitment material flyer_redacted) targeting healthy volunteer recruitment in the Netherlands; recruitment arrangements document (K1_Recruitment arrangements) associated with the Netherlands site.

Netherlands

Earliest CTIS Part Ii Submission Date

16-04-2024

Latest Decision Or Authorization Date

28-04-2025

Processing Time Days

377

Number Of Sites

1

Number Of Participants

52

Primary sponsor

Full Name

Stichting Radboud University Medical Center

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands