FAQs

COVID-19 Vaccination

  • The Add-Aspirin Trial Management Group encourages everyone on the Add-Aspirin trial to have a Covid vaccine if they are advised to do so by their hospital doctor or GP. Add-Aspirin trial participants should tell the nurse or doctor that administers the vaccine that they may be receiving aspirin. There can be some bruising associated with an intramuscular injection. Add-Aspirin trial participants who are already experiencing any bruising or minor bleeding should inform the vaccination team before the vaccination is administered. Add-Aspirin trial medication can be withheld (for example 5 days either side of the vaccination) if there are any specific concerns.

 

RECRUITMENT

  • Since June we have been working towards re-opening the trial to recruitment at centres that have capacity to restart, and now a total of 114 sites have re-opened to recruitment.
  • Following local assessment of research capacity and risks, sites that are able to re-start recruitment must complete the ‘Add-Aspirin Restarting Recruitment Checklist’ and approval for restart must be received from the MRC CTU before any new participants are approached.
  • Those sites restarting recruitment must be able to conduct the trial as per the protocol schedule (including all relevant blood tests and imaging). We understand that some visits may still be delayed or missed due to individual patient factors or patient choice and these should be recorded as previously advised below.
  • At the time of registration (and randomisation), the risks to the individual participant and the likelihood of them being able and willing to adhere to the treatment and follow-up schedule in the current circumstances should be carefully considered in the decision to proceed.
  • If your site re-opened to recruitment following the 2020 suspension, but is now pausing recruitment activity again, please let us know.

 

TAKING CONSENT

  • Consent can be taken by telephone/video call at both registration and randomisation provided there are two delegated individuals on the call to verify the consent at site, and the whole process is documented in writing in the source notes.
  • UK/ROI: Consent forms for patients who verbally consent do not need to be sent to MRC CTU at this time. Patients who verbally consent should fully complete the consent form at the first opportunity when it is safe for them to come to clinic, and a file note should be filed with the form to explain the situation. Once the consent form is completed it should be sent to MRC CTU with a copy of the file note, but we understand there might be a significant delay in receiving these forms.
  • India: Where consent is taken remotely, written consent should be taken at the next possible physical visit and the local Ethics Committee should be notified of participants who are consented in this way.

 

PARTICIPANTS APPROACHING RANDOMISATION

  • To proceed to randomisation requires further blood tests, a BP reading, toxicity assessment and consent. Under the current circumstances, this visit can be done remotely. Bloods and BP may be taken elsewhere, e.g. at the GP.
  • Site teams should consider any risks associated with additional blood tests and/or visits. Randomisation should only occur if the safety of the participant can be assured.
  • Randomisation can be delayed for up to 4 weeks (after completion of the 8-week run-in period) as currently written in the protocol.
  • In the UK, the number to call to randomise a participant remains as per our last communication: +44 (0)20 7670 4925.
  • In the ROI and India participants continue to be randomised online as normal.

 

TRIAL TREATMENT

  • In most cases, treatment in the trial should continue as normal with provisions for drug distribution and follow-up assessments as per the guidance below.
  • However, the protocol allows patients to have a break from trial treatment for medical reasons for up to 3 months if needed/deemed appropriate by the treating clinician. If relevant, please document this on the appropriate follow-up CRF.
  • A number of regulatory agencies have now confirmed that there is currently no scientific evidence establishing a link between non-steroidal anti-inflammatory drugs (NSAIDs) and worsening of COVID 19.
  • The protocol already recommends that participants take paracetamol rather than NSAIDs for relief of flu symptoms.
  • It is hoped that the trial will be able to inform research around the role of anti-coagulation in relation to COVID-19 (through a small number of additional questions on the follow-up CRFs).

 

PROVISIONS FOR IMP

  • As previously advised, we do allow pharmacies to post out medication to patients (but, unfortunately, we are not able to provide reimbursement for this). Where this is not routine practice, verbal consent from the patient to provide their address to the courier must be obtained and documented. The nominated address for the delivery should be recorded in the patient’s notes.
  • In the UK and India, drug can be posted by any method deemed suitable by site, provided mechanisms are in place to confirm receipt by the patient. Temperature monitoring is not required.
  • In the Republic of Ireland IMP should be sent to patients by courier only.
  • Where participants are self-isolating or in quarantine, arrangements for a nominated person to collect drug packs can be made with the participant’s verbal consent.
  • As a last resort, breaks of up to 3 months from trial treatment can also be utilised if patients cannot be posted/collect their medication. Please document this on the appropriate follow-up CRF.

 

PATIENT MANAGEMENT AND FOLLOW-UP ASSESSMENTS

  • Follow-up visits can be conducted via phone wherever necessary and this is preferable to postponing them.
  • Those sites restarting recruitment must be able to conduct the trial as per the protocol schedule (including all relevant blood tests and imaging).
  • However, we appreciate that some visits will need to be postponed (and will fall outside of the stipulated visit windows) – please document where this occurs and let us know.
  • For phone follow-up, sites should annotate next to any missed assessments (e.g. blood tests, scans, BP) to confirm the reason they have been missed and these will not be queried as missing data. The protocol already allows a window of +/- 6 months for imaging.
  • For patients who have been on the study for over a year, one BP measurement in the last year is required for ongoing dispensing of trial medication providing there has been no change in the clinical scenario/potential risks. If a patient has not had a reading in the last year please contact the MRC CTU for advice.
  • Where blood tests cannot be performed patients can continue on trial treatment provided there is no clinical concern, and the patient does not have a history of low eGFR (<45) or low platelets (<50). If no mandatory blood tests have been performed for a year every effort should be made to obtain an up-to-date blood test. Where this is not possible, a break of up to 3 months in trial treatment should be considered where there is clinical concern.
  • If blood pressure (BP) cannot be recorded for patients considered to have a higher risk of raised BP, including those with a history of hypertension, or those where previous BP readings have been close to (within 10mHg) or have met the threshold of ≥160mmHg and/or ≥100mmHg, a break in treatment should be considered until BP can be confirmed to be <160/100. Home BP readings are accepted as confirmation and BP readings within 1 year are acceptable. Where BP readings have not been possible for 1 year, a break of up to 3 months in trial treatment should be considered where there is a clinical concern.
  • If you are aware of a confirmed case of COVID-19 in a trial participant, please report this on a SAE form.

 

SAMPLE COLLECTION – UK only

  • Our biobanks are now re-open to receive samples from approved UK centres.
  • All centres will be required to complete the 'Add-Aspirin Restarting Sample Collection Checklist' prior to sending any samples. This will be reviewed and approved by MRC CTU and shared with the allocated biobank to confirm permission to restart sample collection.
  • Where 3-month urine samples were missed these can be collected at a later follow up visit (if the patient remains on trial treatment). We may contact you to request these samples.
  • If your centre is not yet open to recruitment (or not planning to re-open), you should still complete the checklist to allow the submission of any outstanding tumour blocks.

 

CONTACT WITH THE CTU TEAM / RETURNING DATA

  • The CTU team are all working remotely but can still be contacted on the normal numbers and via the trial mailbox.
  • Wherever possible, please scan CRFs and consent forms and send them to us via fax (+44 (0)20 7670 4818) or via Galaxkey (if you do not already have an account please let us know and we can set you up with one). If this is not possible please continue to post them.
  • If you have scanned and sent CRFs via Galaxkey or fax you do not need to post these CRFs as well. CRFs should only be sent to us once.
  • As noted above and in our previous correspondence, the line for randomisation has changed: please call +44 (0)20 7670 4925.

Raised LFTs/CEA

1. My patient has LFTs greater than 1.5x ULN, are they still eligible?


Provide the trial team with the following:

  • All the most recent consecutive LFT values, including ALT, AST, bilirubin, and ALP dates, and your sites ULN for each LFT provided
  • Has the patient had any imaging of the liver, and if so when was it and did it suggest any possibility of liver metastases?
  • Is there thought to be another cause of raised LFTs, e.g. is chemotherapy ongoing?
  • Also, for the breast cohort: is the patient receiving hormone or HER2 based therapy?
  • For the prostate cohort: can you provide the most recent PSA value?
  • For the colorectal cohort: can you provide the most recent CEA value?
  • If ALP is raised, has the patient had any imaging to exclude bone metastases

Once this information has been given to the trial team, a clinical decision will be made as to whether the patient is eligible for the trial, on a case by case basis.

2. My patient has CEA greater than 1.5x ULN, are they still eligible? 

Provide the trial team with the following:

  • All the recent consecutive CEA levels and dates (including pre/post op) and your sites ULN for CEA
  • The full staging details
  • Confirm that there are no suspicious areas on CT (e.g. indeterminate lung nodules etc.) and no peritoneal disease seen at surgery
  • Has the patient had any additional imaging (e.g. liver MRI, ultrasound or repeat staging CT post treatment)
  • Is there another potential cause for the raised CEA (e.g. is the patient a smoker, history of liver disease)

3. My patient is taking another drug, does this make them ineligible for the trial? 

First, please check Appendix 1 of the protocol for a list of non-permitted medications. If the drug is not listed and there is still 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.

4. Can individuals participating in another trial register in Add-Aspirin?

Please check the list of approved trials for co-enrolment on the Add-Aspirin trial website, if you cannot find the queried trial please contact the trial team with information of the proposed co-enrolment trial. Please endeavour to do this ahead of registering the patient as the trial team cannot always approve co-enrolment immediately. Approval for co-enrolment is only required for interventional studies. Co-enrolment with observational studies is permitted and does not need to be reported.

5. My patient has been diagnosed with two concurrent tumours (breast cohort). Are they eligible for the trial?

We allow concurrent or synchronous tumours from the same cohort entry into the trial, as long as both are treated with curative intent. Staging should be taken from the worst prognosis tumour. Metachronous tumours however (two tumours developing at different time points/ separate occurrences) are not eligible. Bilateral breast cancers are also not eligible.

6. What is the pre-treatment and pathological staging?

The pre-treatment staging is the clinical/radiological staging (prior to surgery). The pathology staging is the histological staging following surgery.

1. Who can take consent?

In the UK, we allow any member of site staff to take trial consent providing they have been delegated to do so by the study PI and are listed on the delegation log with the responsibility to take consent.

2. Where can I get tips/advice on recruiting to the trial?

Please refer to our section ‘Recruitment Tips for Centres’ on the Add-Aspirin website: http://www.addaspirintrial.org/information-for-centres/

We also have clinic posters stored in the members’ area of the website for individual cohorts and one listing all 4 cohorts.

3. I have identified a potential participant but they are not currently being seen in clinic – can I send them information about the trial in the post?

A trial specific Cover Letter has been developed to allow for the Participant Information Sheet to be posted out to patients who are not regularly seen in clinic. This will provide the patient with all the information they need about the study and contact details of their research nurse if they are interested in taking part. Similarly, a Patient Introductory Leaflet has been developed which can be used in a similar way – for example given to Clinical Nurse Specialists who can pass it onto potential participants.

4. How soon after primary treatment can a patient be registered?

Breast Cohort

  1. Surgery and no adjuvant chemotherapy or radiotherapy planned: the run-in period can start between 6 and 12 weeks after definitive surgery (defined as wide local excision or mastectomy).
  2. Surgery and adjuvant chemotherapy (no radiotherapy planned): the run-in period should start after chemotherapy has ended (e.g. day 21 of a 3 week cycle) and no later than 6 weeks after the end of chemotherapy.
  3. Surgery and adjuvant radiotherapy (no chemotherapy planned): the run-in period can start 6 weeks after surgery (radiotherapy may be ongoing) and no later than 6 weeks after the last fraction of radiotherapy.
  4. Surgery and adjuvant chemotherapy followed by adjuvant radiotherapy: the run-in period should not be started until the chemotherapy has ended (e.g. day 21 of a 3 week cycle) and no later than 6 weeks after the final fraction of radiotherapy.

 

Colorectal Cohort

  1. Surgery and no adjuvant chemotherapy or radiotherapy planned (but may have been preceded by chemotherapy or radiotherapy): the run-in period should start between 6 and 12 weeks after definitive surgery.
  2. Surgery and adjuvant chemotherapy (no radiotherapy planned): the run-in period can start after 6 weeks of chemotherapy providing that the platelet count on day 1 of the preceding chemotherapy cycles is >100 x 109/L. The run-in period should start no later than 6 weeks after the end of chemotherapy (e.g. day 14 of a 2 week cycle or day 21 of a 3 week cycle).
  3. Surgery and adjuvant radiotherapy (no chemotherapy planned): the run-in period can start 6 weeks after surgery (radiotherapy may be ongoing) and no later than 6 weeks after the last fraction of radiotherapy.
  4. Surgery and adjuvant chemotherapy followed by adjuvant radiotherapy: the run-in period can start after 6 weeks of chemotherapy providing platelet counts as defined in (b) above. The run-in period should start no later than 6 weeks after the last fraction of radiotherapy.

 

Gastro-oesophageal Cohort

  1. Surgery and no adjuvant chemotherapy or radiotherapy planned (but may have been preceded by chemotherapy): the run-in period should start between 6 and 12 weeks (in India) or 6 and 14 weeks (in the UK) after definitive surgery.
  2. Surgery and adjuvant chemotherapy: the run-in period can start after 6 weeks of chemotherapy providing that the platelet count on day 1 of the preceding chemotherapy cycles is >100 x 109/L. The run-in period should start no later than 6 weeks (in India) and 8 weeks (in the UK) after the end of chemotherapy (day 21 of a 3 week cycle).
  3. Definitive chemoradiation: the run-in period can start as soon as this is complete and no later than 12 weeks (in India) and 14 weeks (in the UK) after the final fraction of radiotherapy. Where a post-treatment endoscopy is routinely performed at 12 weeks after chemoradiotherapy, the run-in period can start once this has been undertaken and up to four weeks after (UK only).

 

Prostate Cohort

  1. Prostatectomy and no adjuvant chemotherapy or radiotherapy planned: the run-in period should start between 6 and 12 weeks after definitive surgery.
  2. Prostatectomy and adjuvant radiotherapy: the run-in period should start at least 6 weeks after surgery and no later than 6 weeks after the last fraction of radiotherapy.
  3. Radical radiotherapy: the run-in period can start as soon as this is complete and no later than 12 weeks after the final fraction of radiotherapy.
  4. Salvage radiotherapy following previous prostatectomy (irrespective of previous therapy): the run-in period should start no later than 12 weeks after the final fraction of radiotherapy.

 

India only - Example of a scenario where you may have the need to register a patient earlier than the timelines stipulated in the defined timelines for entry:

I have a patient in clinic 3 weeks after their curative surgery and I would like to register them in the trial but they have not yet become eligible, as per the timing for entry window. They live very far away and will not be able to return to the hospital to be registered at 6 weeks post-surgery (i.e. once they have become eligible).

Please take the patient’s consent and pre-registration bloods when you see them early post-surgery. When the patient becomes eligible (e.g. 6 weeks after surgery), register them online. The run-in medication can then be posted out to the patient.

1. Do you allow any flexibility for the length of the run-in period?

The run-in period can last between 7-9 weeks. Providing the patient meets the 80% or above adherence without any aspirin related toxicities they can be randomised at any point between 7-9 weeks after registration. For any treatment breaks between the end of run-in and randomisation please contact the trial team for approval.

2. My patient has not taken enough of their run-in tablets but would still like to continue in the trial – what are the options?

The study allows for 4 week or 8 week run-in extensions where new treatment packs will be allocated. Run-in extensions must be formally approved by the trial team and can be discussed on a case by case basis. Whether or not a patient is going to have a run-in extension, the end of run-in visit at 7-9 weeks should still take place (and CRF7 should be completed for all patients). At that point it will be assessed whether a patient is suitable for a run-in extension. If a run-in extension takes place a form 7a should be completed at the end of the 4 or 8 week extension period.

3. My patient has had some mild toxicity during the run-in period – can they continue in the trial?

You should refer to the protocol for any unacceptable toxicities which make patients ineligible to continue, however most low-grade toxicities do not require the participant to stop taking trial medication. If deemed appropriate, please discuss any treatment breaks during the run-in period with the Add-Aspirin trial team. Please provide as much clinical information around the toxicity when e-mailing the trial team.

4. How long after being registered should the patient start the run-in?

The run-in medication should be started as soon as the patient has been registered into the study.

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[1]: 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.

1. How do I allocate drug for a patient I have just registered or randomised?

Once you have registered or randomised a patient into the study, please log into the Drug Supply Management System (DSMS) and click the ‘Drug Allocation’ button on the home screen and then click the ‘Allocate Drug for this Visit’ red button at the top of the screen. Complete all of the required information on the new page, ensuring to select the correct visit (Visit 1 for registration, and Visit 2 for randomisation). Please note that ‘Dosage Reduction’ should only be answered ‘Yes’ if it has been agreed with the trial team that the patient should have their dosage reduced. Once all the information is complete press ‘1 - Get Pack Numbers’, then ‘2 - Confirm’, followed by ‘3 - Print Confirmation’. Only once the packs have been confirmed in step 2 can the drug be given to the patient; if ‘Confirm’ is not clicked, the allocation won’t be complete and packs should not be removed from pharmacy until this is done.

2. Can trial drugs be posted if the participant is not attending clinic?

Where participants are unable to attend clinic visits and visits are conducted over the phone the trial medication can be posted to the participant, however where possible face-to-face visits are encouraged.

1. Do you allow any flexibility for the timing of follow-up visits?

For follow-up visits, a window of plus or minus 2 weeks either side of the scheduled time point is allowed, which gives 4 weeks in which to see the patient for their follow-up assessment. For example, if the patient was randomised on 1st October 2016 and their 12 month visit is due on 1st October 2017; the patient can be seen anytime from 17th September – 15th October 2017. Note to try and stick to visit schedule as the drug ordering is calculated based on when patients should be coming back into clinic. So if they’re brought in earlier you run the risk of not having enough drug to dispense. Where a patient's visit comes outside the protocol schedule, please re-align with randomisation date at the next visit.

2. Do you allow any flexibility for the timing of CTs/colonoscopies/mammograms?

Imaging procedures (CTs/colonoscopies/mammograms) can take place 6 months either side of the specified time-point at which they are required to help align with standard practice. In the colorectal cohort, if the colonoscopy schedule doesn’t fit with local practice, one of the three colonoscopies can be omitted (but note than the 60 month colonoscopy is mandatory)

3. My patient is not due to come into clinic, can a follow-up assessment be conducted over the telephone?

Telephone follow-up visits are permitted where there is no clinic visit planned, providing that all the required information can be obtained and the protocol schedule is followed. Where available, results from clinic visits and GP appointments can be used (e.g. blood pressure readings, blood test results). It is required that Registration and Randomisation visit are conducted in clinic.

4. My patient has stopped their trial treatment early, what follow-up information should be collected?

Should early cessation of trial treatment occur, the patient should be followed up at the same follow-up time points as they would if still taking trial medication. All information listed on the Trial Follow-Up CRF should be completed and where information is not available please mark ‘No’ on that section (e.g. sections on ‘adherence’ and ‘withholding trial treatment’).

5. My patient does not want to continue attending follow-up visits since they are no longer taking trial treatment, what are my options?

Wherever possible, follow-up should continue with clinic visits in accordance with the protocol follow-up schedule to allow the maximum amount of data to be collected. Telephone follow-up visits are also permitted and can be offered to the patient provided adequate provisions have been made to ensure assessments are performed as per protocol
If a participant no longer wishes to have any kind of formal trial follow-up visits, but is happy for their data to be collected from their notes, this is possible and bears no burden on the patient in terms of visits or phone calls. This constitutes a level 2 withdrawal (see the trial Withdrawal Guidance document in the members’ area for further details). Follow-up and disease-specific follow-up CRFs should still be completed at each time point utilising any available data for the participant. Particular attention should be given to key outcome data relating to the patient’s cancer which will normally be available from clinic visits conducted as part of standard care. You should clearly indicate on these CRFs if they are based on routine data, by ticking ‘no’ to Q1a. To ensure the integrity of the trial data, we aim to collect as much information as is available for participants who have withdrawn, but appreciate that this may vary. As such, missing data on the CRFs will not normally be chased where this level of withdrawal is indicated.

6. My patient has come off trial treatment, which protocol assessments are mandated?

Where a participant has stopped trial treatment, trial follow-up should normally continue in accordance with the protocol - most protocol assessments are still expected to take place, though those performed for the purpose of safety monitoring whilst on treatment can be omitted (see table). If the participant has indicated that they no longer want to attend trial-specific follow-up (level 2 withdrawal), data on protocol-specified assessments should be reported - wherever available - from other sources. However, it is accepted that this data will vary, and so assessments are not mandated. Please see our Withdrawal Guidance document in the members' area for further advice on follow-up options for these participants. See the below table as to which assessments are mandated at each level:

 

On Treatment

Off treatment, continuing trial follow-up

(Level 1 withdrawal)

Off treatment and no longer attending trial-specific follow-up

(Level 2 withdrawal)

Off treatment and withdrawn consent for future follow-up

(Level 3 & 4 withdrawals)

Weight

Yes

No

No

No

Blood pressure

Yes

No

No

No

FBC, LFT, U&E & eGFR

Yes

No

No

No

CRP

Yes

No

No

No

Fasting Lipid Profile

Yes

No

No

No

CEA (Colorectal Cohort)

Yes

Yes

No*

No

PSA (Prostate cohort)

Yes

Yes

No*

No

Colonoscopy (Colorectal Cohort)

Yes

Yes

No*

No

CT (Colorectal Cohort)

Yes

Yes

No*

No

Mammogram (Breast Cohort)

Yes

Yes

No*

No

*Whilst trial specific tumour marker bloods or imaging are not mandated for Level 2 withdrawal, if these have been performed as per standard of care they should be reported on the Follow-up CRFs. If any additional assessments have been done (e.g. blood pressure, FBC) these may be reported.

1. What samples need to be collected/what is the recompense?

FFPE tumour samples At trial enrolment, once participants have given consent to be registered for Add-Aspirin and to provide a sample, the tumour sample from surgery (or biopsy specimens for those participants who have undergone radical radiotherapy or chemoradiotherapy) should be requested and sent to the central laboratory. No additional tissue samples are required beyond those already taken as part of standard care. Samples will be returned to centres from the central laboratory upon request. A recommended standard payment of £15 per FFPE sample will be provided to NHS sites on receipt of tumour blocks at the biobank and a valid invoice. Please include a list of trial IDs for the patient being invoiced for on, or alongside, the invoice submitted.

Whole blood sample A 10ml blood sample should be taken at registration once participants have given consent to be registered for Add-Aspirin and to provide a sample.

A royal mail safe box will be provided by MRC CTU for postage of blood samples. FFPE tumour samples should be posted in a jiffy bag. Please note that there are two central biobanks in the UK. During the site set-up process, each trial site will be assigned to one of these, and all samples collected for the trial at that site should be sent to the designated biobank. All samples should be sent to the biobank with a copy of the corresponding Sample Collection CRF.

Please refer to the Add-Aspirin Translational Research Manual for further information.

 

Urine Sub-study (participating centres only)

A 10ml urine sample should be taken at selected sites once participants have given their consent at three time-points: registration, the end of the run-in period and the 3 month post-randomisation visit.

The sample taken at registration should be sent along with the whole blood sample in the same royal mail safe box. Additional safe boxes will be provided to centres taking part in the urinary thromboxane study; the following 2 urine samples (at randomisation and 3 month follow-up) should be sent to the biobank in these. A copy of the corresponding Urine Collection CRF should be sent to the biobank with each sample.

Please note that as of February 2020 recruitment into the urine sub-study was paused. Samples from new patients (at registration and randomisation) are no longer required. 3 month samples that are yet to be collected due to remote visits or being missed in error can still be collected at a later time-point provided the patient is still taking trial treatment.


2. Is sample collection mandatory?

Sample collection for the FFPE tumour samples and whole blood samples where the participant has consented is mandatory for all centres. For selected centres who have agreed to take part in the urine sub-study, collection of the urine sample is mandatory where the patient has consented for this sample to be collected.

Contact Details

If you are an individual who is interested in taking part in Add-Aspirin, please talk to your doctor who will be able to consider whether you are suitable for the trial.

For healthcare professionals

Please log into the members area for Add-Aspirin contact details.

Register Interest

For healthcare professionals

If your centre would like to recruit participants to Add-Aspirin, contact us:
mrcctu.add-aspirin@ucl.ac.uk

Register a participant

To RANDOMISE a participant in the UK please call +44 (0)20 7670 4777

To RANDOMISE a participant from Republic of Ireland or India only, please use the 'Register a participant' link above to randomise online. Please make sure to press 'Randomise' once logged in to the server.

Unblind a participant in the UK

Unblind a participant in the RoI

Unblind a participant in India