Ticagrelor in Human Endotoxemia Response to Human Endotoxemia

Radboud University Medical Center

Status: Completed

Conditions: Endotoxemia

Treatments: Drug: Acetylsalicylic acid lysinate; Drug: ticagrelor; Drug: Clopidogrel; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02612480

NL51923.091.14 (Other Identifier)

tica-lps

2014-005537-30 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 40 patients

Sex: Male

Ages: 18 to 35 years old

Volunteers: Accepts Healthy Volunteers

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)

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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40 participants in 4 patient groups, including a placebo group

Ticagrelor and acetylsalicylic acid

Experimental group

Description:

7 day treatment with ticagrelor 2x90mg after a loading dose of 180 mg and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg.

Treatment:

Drug: ticagrelor

Drug: Acetylsalicylic acid lysinate

Clopidogrel and acetylsalicylic acid

Active Comparator group

Description:

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

Treatment:

Drug: Clopidogrel

Drug: Acetylsalicylic acid lysinate

Placebo and acetylsalicylic acid

Placebo Comparator group

Description:

7 day treatment with placebo and acetylsalicyclic acid 1x80mg after a loading dose of 160 mg

Treatment:

Drug: Placebo

Drug: Acetylsalicylic acid lysinate

Placebo

Placebo Comparator group

Description:

7 day treatment with 2 placebos

Treatment:

Drug: Placebo