Endotoxemia
Conditions
Keywords
endotoxin, LPS, ticagrelor, clopidogrel, acetylsalicyclic acid, placebo
Brief summary
Rationale: In patients suffering a myocardial infarction the P2Y12 receptor antagonists prasugrel and ticagrelor improve outcome and prognosis compared to clopidogrel. Moreover, ticagrelor lowers mortality from pulmonary infections and sepsis, which cannot solely be explained by its platelet-inhibiting effect. An effect on the inflammatory response in the setting of acute myocardial might underlie this phenomenon and if substantiated support a novel beneficial mechanism of the new the P2Y12 receptor antagonists. Objective: To study whether ticagrelor, added to acetylsalicylic acid, modulates the inflammatory response to the administration of lipopolysaccharide (LPS) in humans in vivo, and to compare this effect with the P2Y12 antagonist clopidogrel. Study design: Prospective randomized placebo-controlled trial, according to a PROBE design (prospective randomized open blinded-endpoint study). Study population: Forty healthy male volunteers aged ≥ 18 and ≤ 35 years. Intervention (if applicable): Participants will be randomized to receive either placebo (twice daily), acetylsalicylic acid (80 mg once daily, after a loading dose of 160 mg) + placebo (once daily), acetylsalicylic acid (80 mg once daily, after a loading dose of 160 mg) + ticagrelor (90 mg twice daily, after a loading dose of 180 mg) or acetylsalicylic acid (80 mg once daily, after a loading dose of 160 mg)+ clopidogrel (75 mg once daily, after a loading dose of 300mg). Main study parameters/endpoints: Endpoints: area under the curve of the proinflammatory cytokines TNF-alpha, IL6, IL-10, IL1ra IL-8, IL-1β, MCP-1 MIP-1a, MIP-1b en IFN; peak concentrations of the various cytokines; plasma concentration of HMGP1; platelet-monocyte complex formation and markers of platelet function; plasma concentration of adenosine.
Interventions
DRUGticagrelor
7 day treatment of ticagrelor 2dd90mg after a loading dose of 180mg
DRUGClopidogrel
7 day treatment of clopidogrel 1d75mg after a loading dose of 300mg
7 day treatment of acetylsalicyclic acid 1d80mg after a loading dose of 160mg
DRUGPlacebo
7 day treatment with placebo
Sponsors
Radboud University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* Age ≥ 18 and ≤ 35 years * Male * No known current medical/psychiatric diseases
Exclusion criteria
* History, signs or symptoms of any cardiovascular disease * History of chronic obstructive pulmonary disease (COPD) or asthma * History of hemorrhagic diathesis, or any other disorder associated with increased risk of bleeding * Previous spontaneous vagal collapse * Use of any medication * Smoking * Liver enzyme abnormalities (defined as ALAT and/or ASAT \> twice upper limit of normality) * Thrombocytopenia (\<150\*109 /ml) or anemia (haemoglobin \< 8.0 mmol/L) * Any obvious disease associated with immune deficiency * Febrile illness in the week before the LPS challenge * Hypersensitivity to ticagrelor or any excipients * Active pathological bleeding * History of intracranial haemorrhage * History of dyspepsia * quantitative bleeding assessment tool (BAT) score \>3 (see Appendix 1) * Participation in another drug trial or donation of blood 3 months prior, until 3 months after the planned LPS challenge * Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block, third degree atrioventricular block or a complex 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 MDRD \< 60 ml/min)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| concentration plasma TNFalpha (pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| concentration plasma IL-8 (pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
| concentration plasma IL-10 (pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
| concentration plasma IL-1RA (pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
| concentration plasma IL-1beta (pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
| concentration plasma MCP-1(pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
| concentration plasma MIP-1a(pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
| concentration plasma MIP-1b(pg/ml) | measured after challenge with endotoxin at day 7 of medication | — |
| concentration plasma IFNgamma(pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
| plasma adenosine | measured after challenge with endotoxin at day 7 of medication | — |
| platelet monocyte complexes | measured after challenge with endotoxin at day 7 of medication | flowcytometric determination of monocytic load with platelets |
| concentration plasma IL-6 (pg/ml) | measured after challenge with endotoxin at day 7 of medication | measured with Luminex assay |
| platelet reactivity | measured after challenge with endotoxin at day 7 of medication | ex vivo stimulation of platelets with ADP and collagen, response measured as P-selectin and fibrinogen) |
| monocytic tissue factor expression | measured after challenge with endotoxin at day 7 of medication | tissue factor expression on monocytes as measured by flow cytometry |
| monocytic HLA-DR expression | measured after challenge with endotoxin at day 7 of medication | as measured by flow cytometry |
| CD14/16 ratio | measured after challenge with endotoxin at day 7 of medication | measured with flow cytometry |
| platelet von Willebrandfactor expression | measured after challenge with endotoxin at day 7 of medication | measured with flow cytometry |
| VASP-P | difference between measurement prior to start of study drug after challenge with endotoxin at day 7 of medication | ELISA |
| symptoms during endotoxin day | measured after challenge with endotoxin at day 7 of medication | 6 point likert scale |
| blood pressure | measured after challenge with endotoxin at day 7 of medication | mmHg |
| temperature | measured after challenge with endotoxin at day 7 of medication | tympanic temperature |
| platelet neutrophil complexes | measured after challenge with endotoxin at day 7 of medication | flowcytometric determination of neutrophil load with platelets |
Countries
Netherlands
Outcome results
None listed