1. How likely is it that participant will experience bleeding on the trial?
Aspirin has been used for many years and its safety profile is well known. A common concern about aspirin is its association with an increased risk of bleeding, particularly gastrointestinal bleeding.
The risk of serious bleeding events (usually defined as requiring a transfusion or resulting in death) in people who have had cancer is not expected to be different to those given aspirin for other indications including cardiovascular disease. This is one of the key questions that the Add-Aspirin trial aims to answer. The best estimates of the risk of serious bleeding come from a meta-analysis of clinical trials of aspirin for the prevention of cardiovascular disease: The risk of having a serious bleeding event (excluding intracranial bleeding) without taking aspirin (in the control group) is 0.07% per year, and this increases to 0.1% per year in those taking aspirin. Based on this we estimate that during the course of the trial, 11 out of 3400 participants in the control group, and 35 out of 6800 allocated to aspirin, will develop a serious bleeding (excluding intracranial bleeding).
The risk of intracranial bleeding without aspirin (in the control group) was found to be 0.03% per year, and this increases to 0.04% per year in those taking aspirin. Based on this we estimate that during the course of the trial, 5 out of 3400 participants in the control group, and 12 out of 6800 allocated to aspirin will develop intracranial bleeding. It is thought that the small increase in risk of bleeding is significantly outweighed by the potential benefits being investigated in the Add-Aspirin trial. The Add-Aspirin protocol includes a number of measures and recommendations to reduce the risk of serious bleeding (see below).
2. What measures are being taken to control risk of bleeding?
a) Eligibility criteria to ensure those at highest risk of bleeding are not included in the trial.
b) The protocol advises permanent discontinuation of trial medication where gastrointestinal bleeding develops or another oral anti-coagulant is prescribed (e.g. warfarin or clopidogrel).
c) The risk of gastrointestinal bleeding whilst taking aspirin increases with both the participant’s age and the dose of aspirin given. Participants >75 years old are at higher risk of bleeding, therefore they will only be allocated to either 100mg aspirin or matched placebo.
d) An 8-week active run-in period will highlight those individuals at higher risk of gastrointestinal symptoms and they will not go on to participate in the main trial.
e) Participants will be provided with a credit-card sized participant card which can inform others of the possibility of aspirin use in case of an emergency.
f) Uncontrolled blood pressure is a major contributing factor in cranial bleeds and blood pressure will be recorded at each follow up visit during the trial with recommendations to hold the trial medication where blood pressure is poorly controlled.
Please refer to question 3 for information on the use of proton pump inhibitors.
3. Do participants need to take a PPI during the trial?
The use of proton pump inhibitors as prophylaxis for gastrointestinal symptoms associated with aspirin is not routinely recommended and is not mandated in the Add-Aspirin protocol. An exception to this is in participants that have undergone an oesophagectomy or partial gastrectomy, where a proton pump inhibitor is recommended for the duration of trial treatment (UK/ROI only). A proton pump inhibitor should also be considered for those over 75 years old and anybody else at increased risk of gastrointestinal symptoms. Where a participant develops dyspepsia whilst on trial treatment, a proton pump inhibitor is recommended, along with a number of lifestyle and medical interventions. Please see protocol for further details.
4. Should cardiac events be managed differently whilst on trial medication?
The treatment of a cardiac event often involves the emergency use of aspirin and/or other anti-platelet medication. If an emergency situation arises during the trial it will not be known whether a participant is already taking aspirin or not (or the dose taken). If a participant is suspected of having a cardiac event, standard treatment should be initiated without delay, and this may include administration of standard doses of anti-platelet therapy where indicated. It is possible that a participant may have taken up to a maximum of 300mg of aspirin earlier that day but, under most circumstances, we expect the risks of not treating a cardiac event to outweigh the potential risks of a higher cumulative dose of aspirin over one day. Local specialist advice should be sought. Where knowledge of the trial treatment allocation would alter clinical practice, unblinding is possible (see below), but, in most cases, this should not be required. The same advice applies to participants who are suspected to have an acute ischaemic cerebrovascular event.
5. What should I do if a participant needs to be unblinded?
Wherever possible, unblinding should be avoided to protect the integrity of the Add-Aspirin trial. Most clinical scenarios can be appropriately managed by assuming that the participant is receiving the highest dose of the active drug (i.e. 300mg aspirin), without the need for unblinding, and discontinuation of treatment (on a temporary or permanent basis) is normally preferable to revealing the treatment allocation. As such, unblinding should only be considered where there is a medical emergency and knowledge of the trial treatment allocation is essential for the immediate clinical management of a participant. During CTU working hours (09:00-17:00 GMT Monday to Friday, excluding public holidays), this should first be discussed with the trial team. For out-of-hours unblinding, the Investigator (or assigned deputy) should have determined that the information is necessary to guide the immediate clinical management of the participant, and that the problem cannot be appropriately managed by assuming that the participant is receiving 300mg of aspirin. In the event of an emergency, and the investigator is unavailable, any clinician can unblind via the website, if knowledge of the treatment allocation is urgent.
Each Investigator will be provided with a password to a secure system (accessible via the Add-Aspirin website www.addaspirintrial.org) where unblinding can be performed in an emergency. They will be responsible for maintaining their password and developing local procedures/SOPs on how the unblinding should be performed (e.g. where the password is stored, who can perform unblinding etc.) The investigator (or assigned deputy) should have determined that the information is necessary to guide the immediate clinical management of the participant, and that the problem cannot be appropriately managed by assuming the participant is receiving 300mg of aspirin. Where unblinding occurs, the reason for the decision to unblind and the parties involved must be documented in the participant’s medical record and on the Unblinding CRF. Treatment identification information should be kept confidential and should be disseminated only to those individuals that need to know to advise the medical management of the participant.
6. When can a participant be unblinded?
Reasons for patient unblinding can include and are not limited to, where a participant requires emergency surgery and the dose of trial medication will alter the course of treatment/surgery that the patient receives. Please see the Unblinding page for further information on unblinding.
7. What if a participant buys their own aspirin OTC?
Aspirin is available for purchase without a prescription, either alone, or in combination with other treatments. Examples of preparations that contain aspirin include (but are not limited to) Nu-seals, Anadin, Beechams powders, Alka-seltzer and Disprin. It is extremely important that participants do not take any over-the-counter aspirin during the course of the trial. This is both to protect the safety of participants, as well as to protect the integrity of the trial.
The risks associated with taking over the counter aspirin should be discussed with participants as part of the consent process, and they should be reminded not to take over the counter aspirin at each follow-up visit. Use of any non-trial medication should be monitored during the course of the trial and reported on the follow-up CRF forms. Where aspirin has been taken over the counter the reason should be established and alternative analgesia prescribed where needed. Where over the counter aspirin use persists, this should be discussed with the trial team.
8. Are treatment breaks allowed, and under what circumstances?
The trial protocol allows for a treatment break of up to 3 months during the blinded phase of the trial. Trial treatment breaks can occur for a number of reasons including the management of mild toxicities and the management of dyspepsia. For any queries relating to toxicity, trial treatment breaks should be considered in the first instance rather than permanent discontinuation of trial treatment.
9. What timeframe do you recommend for withholding trial treatment if the patient is undergoing elective surgery?
It depends on the type of surgery and clinical circumstances. The length of time that trial treatment is withheld before and after surgery should be decided by the surgeon performing the operation, but usually a period of 1 week before the procedure would be sufficient. Trial medication should be recommenced as soon as clinically acceptable.
10. Do participants continue to take their trial medication if they have disease recurrence?
When disease recurrence/progression has occurred, participants should continue to take their allocated trial treatment. Where the Investigator feels that this is not appropriate (for example, if the participant will be receiving another treatment that cannot safely be given alongside the trial medication), this should be documented on the Early Cessation of Trial Treatment CRF and the participant should continue to be followed up in the trial wherever possible.
11. Which assessments are still required if a participant has disease recurrence?
When disease recurrence/progression has occurred and the participant continues to take trial medication, they should have their blood pressure and trial bloods tests done as per protocol to ensure their safety whilst continuing to take trial medication. If they have stopped trial treatment because it is not deemed appropriate to continue or the patient has chosen to stop, trial specific blood pressure and blood tests do not need to be done. In either scenario, as the participant has already progressed, trial specific scans (mammogram in the breast cohort, and colonoscopy and CT in the colorectal cohort) and tumour marker bloods (CEA in the colorectal cohort and PSA in the prostate cohort) do not need to be done.
12. My patient has been prescribed another drug, is this allowed whilst on trial medication?
First, please check Appendix 1 of the protocol for a list of non-permitted medications. If the drug is not listed and there is a concern, local judgement should be exercised, but if still unsure, please email the MRC CTU team with the reason behind the uncertainty and the team will be able to advise.
13. A participant has noticed a difference in the size of the tablets – will they be able to guess which treatment they are on?
Although there is a slight difference in the size of some of the trial treatment it is not possible for the participant to become unblinded from the size difference and to work out whether they are on active drug or placebo, as each dose comes with a matching placebo of equal size.