Ticagrelor in Human Endotoxemia Response to Human Endotoxemia
- Conditions
- Endotoxemia
- Interventions
- Registration Number
- NCT02612480
- Lead Sponsor
- Radboud University Medical Center
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 40
- Age ≥ 18 and ≤ 35 years
- Male
- No known current medical/psychiatric diseases
-
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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ticagrelor and acetylsalicylic acid ticagrelor 7 day treatment with ticagrelor 2x90mg after a loading dose of 180 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg. Ticagrelor and acetylsalicylic acid Acetylsalicylic acid lysinate 7 day treatment with ticagrelor 2x90mg after a loading dose of 180 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg. Placebo Placebo 7 day treatment with 2 placebos Placebo and acetylsalicylic acid Placebo 7 day treatment with placebo and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg Clopidogrel and acetylsalicylic acid Acetylsalicylic acid lysinate 7 day treatment with clopidogrel x75 mg after a loading dose of 300 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg Placebo and acetylsalicylic acid Acetylsalicylic acid lysinate 7 day treatment with placebo and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg Clopidogrel and acetylsalicylic acid Clopidogrel 7 day treatment with clopidogrel x75 mg after a loading dose of 300 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg
- Primary Outcome Measures
Name Time Method concentration plasma TNFalpha (pg/ml) measured after challenge with endotoxin at day 7 of medication measured with Luminex assay
- Secondary Outcome Measures
Name Time Method 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
blood pressure measured after challenge with endotoxin at day 7 of medication mmHg
platelet monocyte complexes measured after challenge with endotoxin at day 7 of medication flowcytometric determination of monocytic load with platelets
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 MCP-1(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)
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 concentration plasma MIP-1b(pg/ml) measured after challenge with endotoxin at day 7 of medication concentration plasma IL-6 (pg/ml) measured after challenge with endotoxin at day 7 of medication measured with Luminex assay
concentration plasma IL-8 (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 MIP-1a(pg/ml) measured after challenge with endotoxin at day 7 of medication measured with Luminex assay
monocytic tissue factor expression measured after challenge with endotoxin at day 7 of medication tissue factor expression on monocytes as measured by flow cytometry
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
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
symptoms during endotoxin day measured after challenge with endotoxin at day 7 of medication 6 point likert scale
Trial Locations
- Locations (1)
Intensive Care Medicine, Radboud University Nijmegen Medical Centre
🇳🇱Nijmegen, Gelderland, Netherlands