The Impact of Aspirin Dose Modification on the Innate Immune Response - Will Lower Dose Aspirin Therapy Reduce the Response to Endotoxin
Condition: Acute Coronary Syndrome
MeSH terms: Acute Coronary Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      Heart attacks are usually caused by clots in a coronary artery, depriving the heart muscle of
      blood. Platelets are the main type of blood cell causing clots to form and physicians
      typically give a combination of two anti-platelet drugs, aspirin and ticagrelor, to treat
      this. However, aspirin and ticagrelor have effects not just on the platelets but also on the
      immune system. The investigator has been investigating the effects of different doses of
      aspirin in heart attack participants when taken alongside ticagrelor, and have found that a
      new, lower dose of aspirin given twice daily, rather than the usual standard dose once daily,
      reduces the tendency to bleed whilst on treatment. The investigators are hoping to study the
      wider effects of different aspirin doses, with and without ticagrelor, and have therefore
      developed this study.

      During the two periods of the study, the investigator will give healthy volunteers a
      combinations of these medications and then stimulate their immune system, in order to see if
      the medications affect the immune response. The study will involve a period of medication for
      10-14 days followed by a day in hospital stimulating the immune system with an injection into
      the bloodstream of a substance known as endotoxin, which causes temporary flu-like symptoms,
      followed by blood and urine tests. The investigator will then repeat the process, after a
      minimum of five weeks, taking a different medication combination and having a further
      endotoxin injection. The investigator will also keep in contact by telephone until 2 weeks
      after the end of the medication to ensure participant remain well.
    

Detailed 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 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.
    

Intervention name(s): Aspirin; Ticagrelor
Intervention type(s): Drug; Drug
Intervention description(s): Aspirin will be allocated in different doses and will be used in conjunction with ticagrelor depending on the arm of the trial the participant is randomised to. The different doses are as follows: 20 mg, 75 mg and 300 mg.; Ticagrelor will be allocated as a single loading dose of 180 mg (2 x 90 mg orodispersible tablets) and will be used in conjunction with aspirin depending on the arm of the trial the participant is randomised to.
Intervention MeSH terms: Aspirin; Ticagrelor
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This trial is a randomised controlled hybrid parallel-group and crossover study.
Masking: None (Open Label)
Primary purpose: Prevention