Clinical trial NCT02612480: Ticagrelor in Human Endotoxemia Response to Human Endotoxemia
Official title: The Effect of Ticagrelor on the Inflammatory Response to Human Endotoxemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Endotoxemia
Keywords: endotoxin
LPS
ticagrelor
clopidogrel
acetylsalicyclic acid
placebo
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2015-11-23
Enrollment: 40
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.


Eligibility criteria: 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)

Primary outcomes:
measure: concentration plasma TNFalpha (pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
Secondary outcomes:
measure: concentration plasma IL-6 (pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: concentration plasma IL-8 (pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: concentration plasma IL-10 (pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: concentration plasma IL-1RA (pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: concentration plasma IL-1beta (pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: concentration plasma MCP-1(pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: concentration plasma MIP-1a(pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: concentration plasma MIP-1b(pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: concentration plasma IFNgamma(pg/ml)
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: plasma adenosine
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: platelet monocyte complexes
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: platelet neutrophil complexes
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: platelet reactivity
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: monocytic tissue factor expression
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: monocytic HLA-DR expression
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: CD14/16 ratio
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: platelet von Willebrandfactor expression
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: VASP-P
timeFrame: difference between measurement prior to start of study drug after challenge with endotoxin at day 7 of medication
measure: symptoms during endotoxin day
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: blood pressure
timeFrame: measured after challenge with endotoxin at day 7 of medication
measure: temperature
timeFrame: measured after challenge with endotoxin at day 7 of medication
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Intensive Care Medicine, Radboud University Nijmegen Medical Centre
state: Gelderland
Study officials:
affiliation: Radboud University Medical Center
name: Peter Pickkers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radboud University Medical Center
name: Niels Riksen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: