The Impact of Aspirin Dose Modification on the Innate Immune Response - Will Lower Dose Aspirin Therapy Reduce the Response to Endotoxin

Summary

Participation Requirements

Description

Potential participants will contact the research team in response to advertisement. the research team will then set up a screening appointment in the Clinical Research Facility (CRF) at the Northern general Hospital. They will be offered the chance to be sent a copy of the Participant information sh...

Potential participants will contact the research team in response to advertisement. the research team will then set up a screening appointment in the Clinical Research Facility (CRF) at the Northern general Hospital. They will be offered the chance to be sent a copy of the Participant information sheet for the study before the screening appointment, otherwise they will receive on arrival to the CRF and will be given as much time as they would like to read this. At the screening appointment (visit 1), a medically qualified member of the research team will discuss with the potential participant the background, rationale, design, requirements and risk of the study. The potential participant will have chance to ask any questions they wish and their understanding of the key points will be checked. If they are then happy to sign the consent form, they will do so and the medically-qualified members of the research team taking consent will also sign this. The participant will receive a copy of the signed form for their records. Once written consent has been obtained, participants will be interviewed to obtain information about their demographic details, medical history and medications. They will undergo a physical examination, have their vital signs and height/weight recorded, and have blood drawn from a vein for safety tests. At visit 2, which should occur within 14 days of visit 1 but not before the results of the safety blood tests are known, ongoing consent, any new adverse events and medication changes will be recorded. Vital signs will be checked and physical examination performed. The research team will review the results of the safety blood tests and, in combination with information collected at visit 1, determine if the participant meets all the inclusion criteria and none of the exclusion criteria, and therefore whether they can proceed to randomisation, which will be performed using an electronic (online) system designed for this purpose, sealedenvelope.com. Participants will be randomised to receive one of the following 8 treatment regimens, for 10 days, during the first period of the study: no drug Ticagrelor 180 milligrams (mg) as a loading dose on the last day Aspirin 20 mg BD Aspirin 20 mg BD, plus ticagrelor 180 mg as a loading dose on the last day Aspirin 75 mg once-daily (OD) Aspirin 75 mg, plus ticagrelor 180 mg as a loading dose on the last day Aspirin 300 mg OD Aspirin 300 mg OD, plus ticagrelor 180 mg as a loading dose on the last day Participants will receive the supply of study medication for the first period and will be instructed when to take this. Aspirin will be supplied as a soluble powder preparation in 100 mg sachets that will be used to prepare 20 mg, 75 mg and 300 mg doses. If required by the study to take aspirin, they will be trained in preparing the correct dose, provided with written illustrated instructions and appropriate equipment for this. They will have blood drawn and urine collected for baseline tests, and will undergo measurements of the bleeding time, whereby an inflatable cuff (of the type used for measuring blood pressure) is inflated to a low pressure around the arm, 3 small cuts in the skin of the forearm are made using sprung lancets designed to minimise discomfort, and the time taken for the cuts to stop bleeding is measured. Participants will then take their allocated study treatment for 10-14 days (medication period 1), and will be asked not to take this on the morning of visit 3. At visit 3, which occur after 10-14 days of study medication, participants will once again attend the CRF, this time for a full day. Ongoing consent, any new relevant adverse events and medication changes will be recorded. Participants will undergo physical examination and check of vital signs to ensure they remain well. An intravenous cannula (of the kind typically used for a 'drip') will be inserted into a vein in each arm. One cannula (cannula A) will be used for blood sampling and the other (cannula B) for injection/infusion throughout the course of the day. Blood will be drawn from cannula A for study tests, bleeding time will be measured and urine collected. Participants will then be asked to take the last dose of study medication for period 1, including, where specified by the protocol, a loading dose of ticagrelor administered in the form of 2 x 90 mg orodispersible tablets. Unused medication will be collected, counted and returned to the Northern General Pharmacy. 30 minutes later, an infusion ('drip') of normal saline will be started through cannula B to ensure participants are well hydrated. This will continue for 3 hours and 30 minutes in total. 30 minutes into the infusion, vital signs will be checked, blood will be sampled from cannula A, bleeding time will be measured and an injection of a weight-adjusted dose of sterile bacterial endotoxin will be given through cannula B. Further blood for study tests will be drawn 0.5, 1, 1.5, 2, 3, 4 and 6 hours after the endotoxin injection. Urine will be collected 1, 2, 4 and 6 hours after the endotoxin injection, Bleeding time will be measured 3 hours after the endotoxin injection. From the time of endotoxin administration until 6 hours after it, participants will be connected to a continuous cardiac monitor, and vital signs will be checked at 0.5, 1, 1.5, 2, 3, 4 and 6 hours after the endotoxin injection. Any reportable adverse events will be recorded throughout the day. At the end of the day (6 hours after endotoxin injection) if feeling well participants will be allowed home, but if there are any concerns arrangements will be made for them to stay later, if necessary overnight, within the CRF or a ward of the Northern General Hospital. The day after visit 3, participants will be contacted by telephone by a member of the research team (visit 4). Ongoing consent, any new relevant adverse events and medication changes will be recorded. If there are any concerns raised by the participant or investigator arrangements will be made for an in-person review by a medically qualified member of the research team in the CRF. There will then be a break in study medication of at least five weeks. This is to ensure that any effects of the endotoxin and/or study medication have completely worn off before the next stage of the trial. At 10-14 days after visit 3, participants will be contacted by telephone by a member of the research team (visit 4). Ongoing consent, any new relevant adverse events and medication changes will be recorded. If there are any concerns raised by the participant or investigator arrangements will be made for an in-person review by a medically qualified member of the research team in the CRF. At visit 6, participants will attend for a clinic visit in the CRF. Ongoing consent, new relevant events and medications changes will be recorded. Vital signs will be checked, physical examination performed and safety blood tests taken. A new set of medication will be provided to the participant, with appropriate training in aspirin dosing if needed. The medication that the participant will be asked to take for the next 10-14 days (medication period 2) will be determined by what they were allocated in medication period 1: If received no drug in period 1, to receive no aspirin in period 2 but receive a loading dose of 180 mg ticagrelor on the last day of period 2 If received no aspirin but received a loading dose of 180 mg ticagrelor on the last day of period 1, to receive no drug in period 2 If received aspirin 20 mg BD but no ticagrelor in period 1, to receive aspirin 20mg BD in period 2 plus a loading dose of 180 mg ticagrelor on the last day of period 2 If received aspirin 20 mg BD plus a loading dose of 180 mg ticagrelor on the last day of period 1, to receive aspirin 20 mg BD and no ticagrelor in period 2. If received aspirin 75 mg OD but no ticagrelor in period 1, to receive aspirin 75 mg OD in period 2 plus a loading dose of 180 mg ticagrelor on the last day of period 2 If received aspirin 75 mg OD plus a loading dose of 180 mg ticagrelor on the last day of period 1, to receive aspirin 75 mg OD and no ticagrelor in period 2. If received aspirin 300 mg OD but no ticagrelor in period 1, to receive aspirin 300 mg OD in period 2 plus a loading dose of 180 mg ticagrelor on the last day of period 2 If received aspirin 300 mg OD plus a loading dose of 180 mg ticagrelor on the last day of period 1, to receive aspirin 300 mg OD and no ticagrelor in period 2. Participants will then take their allocated study treatment for 10-14 days (medication period 2) and will be asked not to take this on the morning of visit 7. Visits 7, 8 and 9 will be another full day visit to the CRF followed by a telephone call the next day and after 10-14 days. These will follow exactly the same process as visit 3, 4 and 5. At this point their involvement in the study will end and they will be thanked for their participation.

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