The impact of aspirin dose modification on the innate immune response - WILL lOWer dose aspirin Therapy ReducE the response to Endotoxin? – (WILLOW TREE)

INTERVENTION: Trade Name: Brilique 90 mg Product Name: Brilique 90 mg Pharmaceutical Form: Orodispersible tablet INN or Proposed INN: Ticagrelor CAS Number: 274693275 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 90‐ Trade Name: Aspegic 100mg Product Name: Aspegic 100mg Pharmaceutical Form: Powder for oral solution INN or Proposed INN: Lysine acetylsalicylate CAS Number: 62952‐06‐1 Other descriptive name: aspirin lysine Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ CONDITION: Acute coronary syndrome ; MedDRA version: 20.0 Level: PT Classification code 10051592 Term: Acute coronary syndrome System Organ Class: 10007541 ‐ Cardiac disorders Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14] PRIMARY OUTCOME: Main Objective: The principal objective of this study is to assess the effects of different aspirin dosing regimens (no aspirin, aspirin 20 milligrams twice‐daily, aspirin 75 milligrams once‐daily or aspirin 300 mg once‐daily) on the levels of the inflammatory protein tumour necrosis factor alpha, during the stimulation of the immune system by intravenous injection of a pro‐inflammatory substance, endotoxin. Primary end point(s): The primary endpoint will be plasma tumour necrosis factor alpha TNF‐a (assessed at 2 hours post‐endotoxin injection) compared between participants receiving no drug, aspirin (aspirin lysine) 20 mg BD, aspirin (aspirin lysine) 75 mg OD and aspirin (aspirin lysine) 300 mg OD. Secondary Objective: The secondary objectives of this study are to assess the effects of different aspirin dosing regimens (no aspirin, aspirin 20 milligrams twice‐daily, aspirin 75 milligrams once‐daily or aspirin 300 mg once‐daily; each given with or without a second drug, ticagrelor) on the levels of a range of inflammatory factors, platelet function and clotting mechanisms, during the stimulation of the immune system by intravenous injection of a pro‐inflammatory substance, endotoxin. Timepoint(s) of evaluation of this end point: Serial measurements from 0 to 6 hours after intravenous endotoxin administration, 10 days after commencing study medication. SECONDARY OUTCOME: ; Secondary end point(s): 1. Plasma interleukin‐6 from 0 to 6 hours after endotoxin administration; ; 2. Area under the curve (AUC) of the graph, from 0 to 6 hours after endotoxin administration, of serum C‐reactive protein; ; 3. Leukocyte count, from 0 to 6 hours after endotoxin administration; ; 4. Serum thromboxane B2, from 0 to 6 hours after endotoxin administration; ; 5. Serum prostaglandin E2, from 0 to 6 hours after endotoxin administration; ; 6. AUC of the graph, from 0 to 6 hours after endotoxin administration, of urine prostacyclin metabolite; ; 7. AUC of the graph, from 0 to 3 hours after endotoxin administration, of bleeding time; ; 8. Mean maximum platelet aggregation responses to arachidonic acid (AA), collagen and adenosine diphosphate (ADP), from 0 to 6 hours after endotoxin administration.; ; ; Secondary endpoints will be compared between:; ; 1. Participants receiving no drug, aspirin (aspirin lysine) 20 mg twice‐daily (BD), aspirin (aspirin lysine) 75 mg once‐daily (OD) and aspirin (aspirin lysine) 300 mg OD.; ; 2. Participants receiving ticagrelor 90 mg BD, aspirin (aspirin lysine) 20 mg BD plus ticagrelor 90 mg BD, aspirin (aspirin lysine) 75 mg OD plus ticagrelor 90 mg BD, and aspirin (aspirin lysine) 300 mg OD plus ticagrelor 90 mg BD.; ; 3. Participants receiving no drug and ticagrelor 90 mg BD.; ; 4. Participants receiving aspirin (aspirin lysine) 20 mg BD, and aspirin (aspirin lysine) 20 mg BD plus ticagrelor 90 mg BD.; ; 5. Participants receiving aspirin (aspirin lysine) 75 mg OD, and aspirin (aspirin lysine) 75 mg OD plus ticagrelor 90 mg BD.; ; 6. Participants receiving aspirin (aspirin lysine) 300 mg OD, and aspirin (aspirin lysine) 300 mg OD plus ticagrelor 90 mg BD.; ; 7. Participants receiving no drug, aspirin (aspirin lysine) 20 mg BD, aspirin (aspirin lysine) 75 mg OD and aspirin (aspirin lysine) 300 mg OD, ticagrelor 90 mg BD, aspirin (aspirin lysine) 20 mg BD plus ticagrelor 90 mg BD, aspirin (aspirin lysine) 75 mg OD plus ticagrelor 90 mg BD, and aspirin (aspirin lysine) 300 mg OD plus ticagrelor 90 mg BD.; ; Analyses 2‐7 will also be performed for plasma tumour necrosis factor‐a (as secondary endpoints). For further details see section 10 of this protocol.; Timepoint(s) of evaluation of this end point: Serial measurements from 0 to 6 hours after intravenous endotoxin administration, 10 days after commencing study medication. INCLUSION CRITERIA: To participate in this trial, subjects must meet all of the following criteria: 1.Healthy male subjects, or female subjects not of childbearing potential (either surgically sterile or post‐menopausal) 2.Age between 18 and 65 years inclusive 3.Non‐smokers 4.Body mass index (BMI) between 18 and 28 kg/m2 inclusive, with a body weight between 60‐100 kg 5.In good health as determined by a medical history, physical examination, vital signs and clinical laboratory test results, including renal and liver function, and full blood count 6.Provision of informed consent before any trial‐related activity Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this