Ticagrelor in Human Endotoxemia Response to Human Endotoxemia

Endotoxemia Clinical Trial

Official title:

The Effect of Ticagrelor on the Inflammatory Response to Human Endotoxemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02612480
• Other study ID #: tica-lps
• Secondary ID: 2014-005537-30NL
• Status: Completed
• Phase: N/A
• First received: November 3, 2015
• Last updated: December 14, 2015
• Start date: October 2015
• Est. completion date: December 2015

Study information

• Verified date: December 2015
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Endotoxemia

Intervention

Drug:
• ticagrelor
7 day treatment of ticagrelor 2dd90mg after a loading dose of 180mg
• Clopidogrel
7 day treatment of clopidogrel 1d75mg after a loading dose of 300mg
• Acetylsalicylic acid lysinate
7 day treatment of acetylsalicyclic acid 1d80mg after a loading dose of 160mg
• Placebo
7 day treatment with placebo

Locations

Country	Name	City	State
Netherlands	Intensive Care Medicine, Radboud University Nijmegen Medical Centre	Nijmegen	Gelderland

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	concentration plasma TNFalpha (pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma IL-6 (pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma IL-8 (pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma IL-10 (pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma IL-1RA (pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma IL-1beta (pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma MCP-1(pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma MIP-1a(pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma MIP-1b(pg/ml)		measured after challenge with endotoxin at day 7 of medication	No
Secondary	concentration plasma IFNgamma(pg/ml)	measured with Luminex assay	measured after challenge with endotoxin at day 7 of medication	No
Secondary	plasma adenosine		measured after challenge with endotoxin at day 7 of medication	No
Secondary	platelet monocyte complexes	flowcytometric determination of monocytic load with platelets	measured after challenge with endotoxin at day 7 of medication	No
Secondary	platelet neutrophil complexes	flowcytometric determination of neutrophil load with platelets	measured after challenge with endotoxin at day 7 of medication	No
Secondary	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	No
Secondary	monocytic tissue factor expression	tissue factor expression on monocytes as measured by flow cytometry	measured after challenge with endotoxin at day 7 of medication	No
Secondary	monocytic HLA-DR expression	as measured by flow cytometry	measured after challenge with endotoxin at day 7 of medication	No
Secondary	CD14/16 ratio	measured with flow cytometry	measured after challenge with endotoxin at day 7 of medication	No
Secondary	platelet von Willebrandfactor expression	measured with flow cytometry	measured after challenge with endotoxin at day 7 of medication	No
Secondary	VASP-P	ELISA	difference between measurement prior to start of study drug after challenge with endotoxin at day 7 of medication	No
Secondary	symptoms during endotoxin day	6 point likert scale	measured after challenge with endotoxin at day 7 of medication	No
Secondary	blood pressure	mmHg	measured after challenge with endotoxin at day 7 of medication	No
Secondary	temperature	tympanic temperature	measured after challenge with endotoxin at day 7 of medication	No