We will investigate the effects of acetylsalicylic acid on immunoparalysis following human endotoxemia in healthy male volunteers
Conditions
Interventions
Trade Name: Acetylsalicylzuur Cardio Teva 80 mg
Pharmaceutical Form: Dispersible tablet
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use
Sponsors
Radboudumc
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: - Written informed consent - Age =18 and =35 yrs - Male - Healthy (as confirmed by medical history, examination, ECG, blood sampling) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: • Use of any medication • Use of ASA within 6 weeks prior to the first endotoxemia day • Smoking • Known anaphylaxis or hypersensitivity to acetylsalicylic acid or non-investigational products • History or signs of atopic syndrome (asthma, rhinitis with medication and/or eczema) • History of hematological disease • Thrombocytopenia (3 • History, signs or symptoms of cardiovascular disease, in particular: • Previous spontaneous vagal collapse • History of atrial or ventricular arrhythmia • Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complete left bundle branch block • Hypertension (defined as RR systolic > 160 or RR diastolic > 90) • Hypotension (defined as RR systolic 120 µmol/l) • Liver enzyme abnormalities (above 2x the upper limit of normal) • Medical history of any disease associated with immune deficiency • CRP > 20 mg/L, WBC > 12x109/L or < 4 x109/L, hemoglobin < 8 mmol/L or clinically significant acute illness, including infections, within 4 weeks before the first endotoxemia day • Previous (participation in a study with) LPS administration • Participation in a drug trial or donation of blood 3 months prior to first endotoxemia day • Any vaccination within 3 months prior to the first endotoxemia day until the end of the study • Recent hospital admission or surgery with general anesthesia (<3 months to endotoxemia day) • Use of recreational drugs within 21 days prior to the first endotoxemia day • Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To determine whether acetylsalicylic acid treatment can reverse endotoxin tolerance, which is expressed as a decrease in pro-inflammatory cytokine levels between the first and second endotoxin challenge.;Secondary Objective: 2. To determine whether acetylsalicylic acid prophylaxis can prevent endotoxin tolerance, which is expressed as a decrease in pro-inflammatory cytokine levels between the first and second endotoxin challenge. 3. To determine whether ASA treatment and prophylaxis modulate the absolute plasma cytokine levels upon the second endotoxin challenge. 4. To determine the effects of treatment and prophylaxis with acetylsalicylic acid on ex vivo responsiveness of whole blood and peripheral blood mononuclear cells to various inflammatory stimuli. 5. To determine the effects of treatment and prophylaxis with acetylsalicylic acid on cell surface expression of markers of immunoparalysis on circulating leukocytes, including but not limited to HLA-DR, PD-L1, PD-1, and IL-7R. 6. To determine the effects of treatment and prophylaxis with acetylsalicylic acid on plasma and urine levels of prostaglandin E2.;Primary end point(s): The primary study endpoint, endotoxin tolerance, is the decrease in the area under the curve (AUC) of the plasma TNFa concentration between the first and second endotoxin challenge in the control group compared to the treatment group. ;Timepoint(s) of evaluation of this end point: AUC of TNFa on endotoxemia day 7 and day 14. AUC is estimated using blood sampling at timepoints (relative to LPS administration): -60; 0; 30; 60;90; 120;150; 180;210; 240; 360; 480. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Plasma levels of other inflammatory mediators on the first and second endotoxemia day (including but not limited to TNFa, IL-6, IL-8, IL-10, IL-1RA) - Ex vivo production of inflammatory mediators and reactive oxygen species (ROS) by whole blood and peripheral blood mononuclear cells (PBMCs) stimulated by LPS and several pathogens (including but not limited to S. aureus, M. tuberculosis, C. albicans) - Monocyte surface antigen expression (including but not limited to mHLA-DR, Programmed Death Ligand (PDL)-1, Programmed cell Death protein (PD)-1, IL-7R) - Plasma thromboxane B2 levels, as an expression of thromboxane A2 - Prostaglandin E2 urine metabolites (PGE-M) - Kidney damage markers in urine (including but not limited to NGAL, KIM-1, L-FABP) - Transcriptional activity of leukocytes - Symptom score - Mean arterial pressure - Heart rate - Temperature ;Timepoint(s) of evaluation of this end point: Evaluation of endpoints is done on both endotoxemia day 7 and day 14. Using blood sampling at timepoints (relative to LPS administration): -60; 0; 30; 60;90; 120;150; 180;210; 240; 360; 480. | — |
Countries
Netherlands
Contacts
Public ContactResearch IC, office of Guus Leijte
Radboudumc
Outcome results
None listed