Ticagrelor in Human Endotoxemia Response to Human Endotoxemia

The Effect of Ticagrelor on the Inflammatory Response to Human Endotoxemia

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 Overview

• Status: Completed
• Conditions: Endotoxemia
• Intervention / Treatment: Drug: ticagrelor; Drug: Acetylsalicylic acid lysinate; Drug: Clopidogrel; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500HB
      • Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Peter Pickkers, MD, PhD, Radboud University Medical Center; Principal Investigator: Niels Riksen, MD, PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: November 3, 2015
• First Submitted That Met QC Criteria: November 19, 2015
• First Posted (Estimate): November 23, 2015

Study Record Updates

• Last Update Posted (Estimate): December 15, 2015
• Last Update Submitted That Met QC Criteria: December 14, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: placebo; ticagrelor; clopidogrel; LPS; endotoxin; acetylsalicyclic acid
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Bacteremia; Toxemia; Endotoxemia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Ticagrelor; Clopidogrel; Acetylsalicylic acid lysinate
• Other Study ID Numbers: tica-lps; 2014-005537-30 (EudraCT Number); NL51923.091.14 (Other Identifier: CCMO)