The Effect of Ticagrelor on the Inflammatory Response to Human Endotoxemia
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- concentration plasma TNFalpha (pg/ml)
Study Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Basic Science
- Masking
- Single (Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 35 Years (Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Age ≥ 18 and ≤ 35 years
- •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
- •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)
Arms & Interventions
Ticagrelor and acetylsalicylic acid
7 day treatment with ticagrelor 2x90mg after a loading dose of 180 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg.
Intervention: ticagrelor (Drug)
Ticagrelor and acetylsalicylic acid
7 day treatment with ticagrelor 2x90mg after a loading dose of 180 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg.
Intervention: Acetylsalicylic acid lysinate (Drug)
Clopidogrel and acetylsalicylic acid
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
Intervention: Clopidogrel (Drug)
Clopidogrel and acetylsalicylic acid
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
Intervention: Acetylsalicylic acid lysinate (Drug)
Placebo and acetylsalicylic acid
7 day treatment with placebo and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg
Intervention: Acetylsalicylic acid lysinate (Drug)
Placebo and acetylsalicylic acid
7 day treatment with placebo and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg
Intervention: Placebo (Drug)
Placebo
7 day treatment with 2 placebos
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
concentration plasma TNFalpha (pg/ml)
Time Frame: measured after challenge with endotoxin at day 7 of medication
measured with Luminex assay
Secondary Outcomes
- platelet von Willebrandfactor expression(measured after challenge with endotoxin at day 7 of medication)
- VASP-P(difference between measurement prior to start of study drug after challenge with endotoxin at day 7 of medication)
- blood pressure(measured after challenge with endotoxin at day 7 of medication)
- concentration plasma IL-10 (pg/ml)(measured after challenge with endotoxin at day 7 of medication)
- concentration plasma IL-1RA (pg/ml)(measured after challenge with endotoxin at day 7 of medication)
- concentration plasma MCP-1(pg/ml)(measured after challenge with endotoxin at day 7 of medication)
- platelet reactivity(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 after challenge with endotoxin at day 7 of medication)
- 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)
- concentration plasma IL-6 (pg/ml)(measured after challenge with endotoxin at day 7 of medication)
- concentration plasma IL-8 (pg/ml)(measured after challenge with endotoxin at day 7 of medication)
- concentration plasma IL-1beta (pg/ml)(measured after challenge with endotoxin at day 7 of medication)
- concentration plasma MIP-1a(pg/ml)(measured after challenge with endotoxin at day 7 of medication)
- monocytic tissue factor expression(measured after challenge with endotoxin at day 7 of medication)
- temperature(measured after challenge with endotoxin at day 7 of medication)
- platelet neutrophil complexes(measured after challenge with endotoxin at day 7 of medication)
- monocytic HLA-DR expression(measured after challenge with endotoxin at day 7 of medication)
- CD14/16 ratio(measured after challenge with endotoxin at day 7 of medication)
- symptoms during endotoxin day(measured after challenge with endotoxin at day 7 of medication)
Investigators
Peter Pickkers
Prof. Dr. Peter Pickkers
Radboud University Medical Center