Ticagrelor in Human Endotoxemia Response to Human Endotoxemia

Study Overview
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Brief Summary
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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.

Official Title
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The Effect of Ticagrelor on the Inflammatory Response to Human Endotoxemia

Conditions
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Endotoxemia

Intervention / Treatment
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* Drug: ticagrelor
* Drug: Clopidogrel
* Drug: Acetylsalicylic acid lysinate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor and acetylsalicylic acid<br>7 day treatment with ticagrelor 2x90mg after a loading dose of 180 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg. | Drug: ticagrelor<br>* 7 day treatment of ticagrelor 2dd90mg after a loading dose of 180mg<br>* Other names: brillique;Drug: Acetylsalicylic acid lysinate<br>* 7 day treatment of acetylsalicyclic acid 1d80mg after a loading dose of 160mg<br>* Other names: Aspirin;|
| Active Comparator: Clopidogrel and acetylsalicylic acid<br>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 | Drug: Clopidogrel<br>* 7 day treatment of clopidogrel 1d75mg after a loading dose of 300mg<br>* Other names: Plavix;Drug: Acetylsalicylic acid lysinate<br>* 7 day treatment of acetylsalicyclic acid 1d80mg after a loading dose of 160mg<br>* Other names: Aspirin;|
| Placebo Comparator: Placebo and acetylsalicylic acid<br>7 day treatment with placebo and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg | Drug: Acetylsalicylic acid lysinate<br>* 7 day treatment of acetylsalicyclic acid 1d80mg after a loading dose of 160mg<br>* Other names: Aspirin;Drug: Placebo<br>* 7 day treatment with placebo<br>|
| Placebo Comparator: Placebo<br>7 day treatment with 2 placebos | Drug: Placebo<br>* 7 day treatment with placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| concentration plasma TNFalpha (pg/ml) | measured with Luminex assay | measured after challenge with endotoxin at day 7 of medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| concentration plasma IL-6 (pg/ml) | measured with Luminex assay | measured after challenge with endotoxin at day 7 of medication | 
| concentration plasma IL-8 (pg/ml) | measured with Luminex assay | measured after challenge with endotoxin at day 7 of medication | 
| concentration plasma IL-10 (pg/ml) | measured with Luminex assay | measured after challenge with endotoxin at day 7 of medication | 
| concentration plasma IL-1RA (pg/ml) | measured with Luminex assay | measured after challenge with endotoxin at day 7 of medication | 
| concentration plasma IL-1beta (pg/ml) | measured with Luminex assay | measured after challenge with endotoxin at day 7 of medication | 
| concentration plasma MCP-1(pg/ml) | measured with Luminex assay | measured after challenge with endotoxin at day 7 of medication | 
| concentration plasma MIP-1a(pg/ml) | measured with Luminex assay | 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 IFNgamma(pg/ml) | measured with Luminex assay | measured after challenge with endotoxin at day 7 of medication | 
| plasma adenosine |  | measured after challenge with endotoxin at day 7 of medication | 
| platelet monocyte complexes | flowcytometric determination of monocytic load with platelets | measured after challenge with endotoxin at day 7 of medication | 
| platelet neutrophil complexes | flowcytometric determination of neutrophil load with platelets | measured after challenge with endotoxin at day 7 of medication | 
| platelet reactivity | ex vivo stimulation of platelets with ADP and collagen, response measured as P-selectin and fibrinogen) | measured after challenge with endotoxin at day 7 of medication | 
| monocytic tissue factor expression | tissue factor expression on monocytes as measured by flow cytometry | measured after challenge with endotoxin at day 7 of medication | 
| monocytic HLA-DR expression | as measured by flow cytometry | measured after challenge with endotoxin at day 7 of medication | 
| CD14/16 ratio | measured with flow cytometry | measured after challenge with endotoxin at day 7 of medication | 
| platelet von Willebrandfactor expression | measured with flow cytometry | measured after challenge with endotoxin at day 7 of medication | 
| VASP-P | ELISA | difference between measurement prior to start of study drug after challenge with endotoxin at day 7 of medication | 
| symptoms during endotoxin day | 6 point likert scale | measured after challenge with endotoxin at day 7 of medication | 
| blood pressure | mmHg | measured after challenge with endotoxin at day 7 of medication | 
| temperature | tympanic temperature | measured after challenge with endotoxin at day 7 of medication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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endotoxin, LPS, ticagrelor, clopidogrel, acetylsalicyclic acid, placebo