WILL lOWer Dose Aspirin be Better With Rivaroxaban in Patients With Chronic Coronary Syndromes?

Description

Recruitment Potential participants will be identified through review of the records of the South Yorkshire Cardiothoracic Centre and/or by referral by their clinical team.

Specifically, participants may be approached in the following ways:

1. An invitation letter sent by post in combination with a copy of the participant information sheet. There will be a reply slip which they can return by post, and there will be contact details (telephone and email) for the research team to allow them to respond by these methods too.
2. Directly by telephone. In this case, should they be happy to learn more, they will be sent a copy of the invitation letter, participant information sheet and reply slip by post or email, depending on their preference. If they agree to attend for study screening, they will communicate this to the research team by returning the reply slip by post or email, or by contacting the research team directly using the contact details provided to them.
3. Directly in clinics within the Cardiology and Cardiothoracic Surgery Directorate at Sheffield Teaching Hospitals NHS Foundation Trust, upon referral from their clinical team. In this case they will be provided with a copy of the participant information sheet and, if unable to decide whether they wish to attend for screening or not during the clinic visit, will be signposted to the contact details of the research team to provide their response.

Potential participants who are interested in taking part in the study will then be contacted by the research team to book a screening appointment.

Screening

Screening will occur at visit 1. The following study procedures will be performed, after obtaining written consent for the study:

• Medical history
• Physical examination
• Collection of demographic data
• Vital signs (pulse, blood pressure and temperature).
• Height, weight and BMI
• Recording of any concomitant medication
• Safety blood tests (13.5 ml blood sample for haematology, clinical chemistry and coagulation)
• Urinalysis (dipstick), plus urinary pregnancy test if female and of childbearing potential. This will also be checked immediately prior to first rivaroxaban exposure at visit 3.
• Baseline electrocardiogram

Consent Written, informed consent, using the current version of the approved designated form for this study, will be obtained prior to any study procedures being carried out. This will be explained and obtained by a medically-qualified member of the research team, listed on the delegation log. Participants will have the chance to read the ICF/PIS for as long as they need, and will be able to ask any questions, prior to signing. Minors and those judged to be without the mental capacity to provide informed consent will not be enrolled into the study.

Participants will remain free to withdraw at any time from the trial, without giving reasons and without prejudicing his/her further treatment, and will be provided with a contact point where he/she may obtain further information about the trial. Samples collected up to the point of withdrawal will only be used after withdrawal if the participant consents for this, otherwise they will be destroyed. However, data collected up to that point will be used for analysis, and this will be explicitly stated in the participant information sheet and consent form.

The randomisation scheme

Participants will be randomised to one of the following two treatment sequences, in a 1:1 fashion:

(A) Aspirin 75 mg OD for 14(-2) days then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD for 14(-2) days then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD or (B) Aspirin 75 mg OD for 14(-2) days then aspirin 75 mg OD plus rivaroxaban 2.5 mg BD for 14(-2) days then aspirin 20 mg BD plus rivaroxaban 2.5 mg BD

Baseline data At visit 1

• Medical history
• Physical examination
• Demographic data
• Vital signs (pulse, blood pressure and temperature)
• Weight and BMI
• Concomitant medication
• Lab safety parameters (full blood count, urea & electrolytes, liver function tests, clotting screen, dipstick urinalysis, urinary pregnancy test if female and of childbearing potential)
• Electrocardiogram findings At visit 2
• Vital signs: pulse, blood pressure and temperature
• Physical examination

Visit 1 - Screening (Day -21 to 0)

Screening of subjects and all study-related procedures will take place in the Sheffield Clinical Research Facility, a specialist environment for the conduct of clinical research. The following assessments and procedures will be performed:

• Full informed consent, including completion of the informed consent form
• Inclusion/exclusion criteria (see section 6)
• Medical history
• Physical examination
• Demographic data
• Vital signs: pulse, blood pressure and temperature
• Weight and BMI
• Concomitant medication
• Lab safety (13.5 ml blood sample for haematology; clinical chemistry & coagulation; urinalysis)
• Electrocardiogram

Visit 2 (Day 0) - Randomisation

• Vital signs
• Physical examination
• Reconfirm eligibility criteria met (by a medically qualified member of the study team, see section 6) and no withdrawal criteria met (section 7.10)
• Randomisation
• Provided with supply of aspirin (aspirin lysine) for periods 1, 2 and 3 (2 boxes of 30 sachets)
• Dose-preparation training for aspirin (aspirin lysine) 75 mg OD, including supply of written illustrated instructions
• Issue with participant information card detailing treatment allocation, restrictions during the study and contact details for the research team

Period 1: 14 (-2) days - Participants will receive aspirin (aspirin lysine) 75 mg OD, but should withhold their dose on the morning of visit 3 (during which the dose will be taken).

Visit 3 - Period 1: Day 14 (-2)

• Vital signs
• Physical examination
• Adverse event recording
• Concomitant medication recorded
• Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, prostanoids and platelet function
• Bleeding time pre- and 2 hours post dose
• Urine sample pre- and 2 hours post-dose for prostanoids
• IMP compliance check for period 1
• Dispensing of rivaroxaban 2.5 mg tablets for periods 2 and 3 (total 56 tablets)
• Urine pregnancy test for women of childbearing potential (must not continue to period 2 if positive)
• Dose-preparation training for aspirin (aspirin lysine) 20 mg BD if allocated to sequence A, including provision of written instructions

Period 2: 14(-2) days

Participants will receive their allocated regimen for period 2 for 14(-2) days:

• If randomised to sequence A they will receive aspirin (aspirin lysine) 20 mg BD plus rivaroxaban 2.5 mg BD in period 2.
• If randomised to sequence B they will receive aspirin (aspirin lysine) 75 mg BD plus rivaroxaban 2.5 mg BD in period 2.

Participants should withhold their dose on the morning of visit 4 (during which the dose will be taken).

Visit 4 : 14(-2) days into period 2 - Physical examination

• Adverse event recording
• Concomitant medication recorded
• Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, prostanoids and platelet function
• Bleeding time pre- and 2 hours post dose
• Urine sample pre- and 2 hours post-dose for prostanoids
• IMP compliance recorded for period 2
• Dose-preparation training for aspirin (aspirin lysine) 75 mg OD if allocated to sequence A or 20 mg BD if sequence B, including provision of written instructions

Period 3: 14(-2) days

Participants will receive their allocated regimen for period 3 for 14(-2) days:

• If randomised to sequence A they will receive aspirin (aspirin lysine) 75 mg OD plus rivaroxaban 2.5 mg BD in period 3.
• If randomised to sequence B they will receive aspirin (aspirin lysine) 20 mg BD plus rivaroxaban 2.5 mg BD in period 3.

Visit 5 : 14(-2) days into period 3 - Vital signs

• Physical examination
• Adverse event recording
• Concomitant medication recorded
• Venous blood sample pre- and 2 hours post-dose for fibrin clot dynamics, inflammatory markers, prostanoids and platelet function
• Bleeding time pre- and 2 hours post dose
• Urine sample pre- and 2 hours post-dose for prostanoids
• IMP compliance recorded for period 3
• Collect and return unused medication to pharmacy
• Transition to standard of care aspirin 75 mg OD, ensuring participant has a supply of this

Visit 6 : 14(-2) days after visit 5 (Telephone call) - Telephone follow-up for adverse events and concomitant medication

Details