E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
We will investigate the effects of acetylsalicylic acid on immunoparalysis following human endotoxemia in healthy male volunteers |
We onderzoeken het effect van acetylsalicylzuur op immuunparalyse volgend op humane endotoxemie in gezonde mannelijke vrijwilligers |
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E.1.1.1 | Medical condition in easily understood language |
We will study the effect of aspirin on an attenuated immune system after human endotoxemia in healthy male volunteers |
We onderzoeken het effect van aspirine op een verzwakt immuunsysteem dat wordt gezien na humane endotoxemie in gezonde mannelijke vrijwilligers |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Written informed consent - Age ≥18 and ≤35 yrs - Male - Healthy (as confirmed by medical history, examination, ECG, blood sampling) |
- Getekend informed consent - Leeftijd ≥18 en ≤35 jaar - Mannelijk geslacht - Gezond (bevestigd door medische geschiedenis, lichamelijk onderzoek, ECG, bloedanalyse) |
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E.4 | Principal 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 (<150*10^9/ml) or anemia (hemoglobin < 8.0 mmol/L) • History of intracranial hemorrhage • Quantitative bleeding assessment tool (BAT) score>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 < 100 or RR diastolic < 50) • Renal impairment (defined as plasma creatinine >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
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• Medicatiegebruik • Gebruik van ASA in de 6 weken voorafgaand aan de eerste endotoxemie dag • Roken • Bekende anafylaxie of overgevoeligheid voor ASA of voor non-investigational products • Voorgeschiedenis van hematologische aandoeningen • Thrombocytopenie (<150*10^9/ml) of anemie (hemoglobin < 8.0 mmol/L) • Voorgeschiedenis van intracraniële bloeding • Kwantitatieve Bleeding Assessment Tool (BAT) score>3 • Voorgeschiedenis, tekenen of symptomen van cardiovasculaire ziekte, in het bijzonder: • Verleden met spontane vagale reactie • Verleden met atriale of ventriculaire aritmieën • Cardiale geleidingsstoornis op ECG (2e graads atrioventriculair block of compleet linker bundeltakblok • Hypertensie (gedefinieerd als systolische RR > 160 of diastolische RR > 90) • Hypotensie (gedefinieerd als systolische RR < 100 of diastolische RR < 50) • Nierfunctiestoornissen (gedefinieerd als plasma kreatinine >120 μmol/l) • Leverenzymafwijkingen (meer dan 2x bovenlimiet) • Voorgeschiedenis van immunodeficiëntie • CRP > 20 mg/L, Leukocyten > 12x109/L of < 4 x109/L, hemoglobine < 8 mmol/L of klinisch significante ziekte, inclusief infecties, in de 4 weken voorafgaand aan de eerste endotoxemie • Eerder deelname aan een LPS-challenge • Deelname aan een geneesmiddelenonderzoek of bloeddonatie in de 3 maanden voorafgaand aan de eerste endotoxemie • Vaccinatie in de 3 maanden voorafgaan aan de eerste endotoxemie • Recente ziekenhuisopname of operatie met algehele anesthesie (< 3 maanden) • Recreatief drugsgebruik in de 21 dagen voorafgaand aan de eerste endotoxemie • Onvermogen tot individueel informed consent (vanwege taal of mentale reden) of onvermogen tot deelname aan studieonderdelen |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary study endpoint, endotoxin tolerance, is the decrease in the area under the curve (AUC) of the plasma TNFα concentration between the first and second endotoxin challenge in the control group compared to the treatment group. |
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E.5.1.1 | 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. |
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E.5.2 | Secondary end point(s) |
- Plasma levels of other inflammatory mediators on the first and second endotoxemia day (including but not limited to TNFα, 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
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |