1.1. Is there a limit on the number of participants a site can recruit?
Recruitment in the TRACK trial is competitive. Sites can recruit as many participants as possible until total recruitment for the trial is completed. There is no upper limit on participant recruitment at any site.
1.2. Can a patient be enrolled in multiple trials?
Yes, co-enrolment in multiple trials is allowed provided the other experimental intervention does not have any interaction with rivaroxaban or is not an antithrombotic agent (antiplatelet medication or anticoagulant).
2.1. Lacunar stroke is an exclusion criterion. How should lacunar and non-lacunar strokes be differentiated on CT scan? Why are patients with lacunar stroke excluded?
2.2. Can a patient scheduled for kidney transplant be enrolled?
2.3. Can a patient on deceased-donor kidney transplant waitlist be enrolled?
2.4. What constitutes significant liver disease?
2.5. Can a patient be enrolled if they have CKD stage 4 or 5 at screening and they are planned for haemodialysis in the coming weeks/months?
2.6. If the patient has CKD due to other diseases like autoimmune disease, can the patient be recruited?
2.7. Can patients with atrial fibrillation be enrolled?
2.8. If the patient’s haemoglobin is < 90 g/L (<9 g/dL), but medication is used to increase their haemoglobin to ≥90 g/L, can they be included in the study?
2.9. If a patient is on P2Y12 inhibitors/ADP receptor inhibitors or phosphodiesterase inhibitors, how long does the patient need to stop these medications before enrolling into the study?
2.10. Is an echocardiogram (ECHO) required to determine ejection fraction for eligibility?
2.11. Can a patient be enrolled if they have a lesion at risk of bleeding due to recent surgery?
2.12. Can a patient already on aspirin be enrolled?
2.13. Can patients with no history of cardiovascular disease be enrolled?
2.14. When is a pregnancy test required?
2.15. Can a patient be enrolled if they have a mechanical/prosthetic heart valve at the time of study enrolment?
2.16. When screening participants for eligibility, can eGFR be calculated from serum creatinine results?
2.1. Lacunar stroke is an exclusion criterion. How should lacunar and non-lacunar strokes be differentiated on CT scan? Why are patients with lacunar stroke excluded?
There is no need for an MRI or a CT scan to rule out exclude lacunar stroke when determining eligibility. If a patient is known to have a history of lacunar stroke (e.g. mentioned in their medical records), only then is the patient ineligible. Rivaroxaban was contraindicated for lacunar stroke in European countries at the time the study was conceived.
2.2. Can a patient scheduled for kidney transplant be enrolled?
Patients scheduled for living-donor kidney transplant surgery are not eligible.
2.3. Can a patient on deceased-donor kidney transplant waitlist be enrolled?
Patients on deceased-donor kidney transplant waitlist are eligible to participate. Please check with their treating nephrologist before enrolling.
2.4. What constitutes significant liver disease?
Patients are ineligible if they have significant liver disease (defined as Child-Pugh Class B or C) or ALT >3 times upper normal limit. Note that two-thirds of the parent drug is metabolised in the liver.
2.5. Can a patient be enrolled if they have CKD stage 4 or 5 at screening and they are planned for haemodialysis in the coming weeks/months?
Yes, the patient can be enrolled.
2.6. If the patient has CKD due to other diseases like autoimmune disease, can the patient be recruited?
Yes, provided they satisfy the eligibility criteria.
2.7. Can patients with atrial fibrillation be enrolled?
Patients with atrial fibrillation require therapeutic anticoagulation using the full dose of the anticoagulant drug for the prevention of stroke. This trial uses a low dose of rivaroxaban that does not provide therapeutic anticoagulation. In the investigator’s opinion, if the patient requires therapeutic anticoagulation for stroke prevention, this patient should be excluded. However, in the investigator’s opinion, if there is clinical equipoise for the prevention of myocardial infarction or peripheral artery disease events using low dose rivaroxaban, this patient could be enrolled at the Investigator’s discretion.
2.8. If the patient’s haemoglobin is < 90 g/L (<9 g/dL), but medication is used to increase their haemoglobin to ≥90 g/L, can they be included in the study?
Yes, erythropoiesis-stimulating agents are allowed to increase their haemoglobin to ≥90 g/L (≥9 g/dL). However, the haemoglobin level must be ≥90 g/L (≥9 g/dL) at the time of enrolment.
2.9. If a patient is on P2Y12 inhibitors/ADP receptor inhibitors or phosphodiesterase inhibitors, how long does the patient need to stop these medications before enrolling into the study?
P2Y12 inhibitors/ADP receptor inhibitors, phosphodiesterase inhibitors and non-study anticoagulants (except regional anticoagulation for haemodialysis) must be stopped at the time of enrolment and prior to starting the run-in phase. The run-in phase of 21 days (14 to 30 days) is designed to serve as a washout period, hence there is no separate washout period required before enrolling patients.
UPDATE: Please note that the protocol lists current treatment using phosphodiesterase inhibitors (dipyridamole) in the exclusion criteria. This has been misinterpreted as any and all phosphodiesterase inhibitors being prohibited with dipyridamole being an example, however, we wish to clarify that the phosphodiesterase inhibitor not allowed are only dipyridamole and cilostazol.
2.10. Is an echocardiogram (ECHO) required to determine ejection fraction for eligibility?
It is not required to perform an echocardiogram to determine ejection fraction. However, if the LV ejection fraction is known to be <30% on a previous echocardiogram, the patient is not eligible.
2.11. Can a patient be enrolled if they have a lesion at risk of bleeding due to recent surgery?
If the patient has recently undergone surgery (in the past 1 month), they are not eligible. It is at the Investigator’s discretion to assess bleeding risk and determine if the patient can be enrolled to the trial.
2.12. Can a patient already on aspirin be enrolled?
Yes, patients already on aspirin are eligible and can continue on aspirin during the trial.
2.13. Can patients with no history of cardiovascular disease be enrolled?
Yes, if they have diabetes mellitus or are older than 65 years.
2.14. When is a pregnancy test required?
A pregnancy test is only required in women of childbearing potential. Women of childbearing potential should use contraception. Section 4.3.6 of the Manual of Operations lists appropriate contraception methods.
2.15. Can a patient be enrolled if they have a mechanical/prosthetic heart valve at the time of study enrolment?
No, this is an exclusion criteria. This does not include patients that have bioprosthetic valves that do not require therapeutic anticoagulation.
2.16. When screening participants for eligibility, can eGFR be calculated from serum creatinine results?
Yes, eGFR can be calculated from serum creatinine results using the CKD-EPI creatinine equation in this simple online calculator http://mdrd.com
3.1. Are blood tests and/or ECGs required during the trial?
3.2. Is laboratory monitoring with coagulation tests required during the trial?
3.3. Is there any difference between rivaroxaban and aspirin in terms of bleeding risk?
3.4. Can participants have COVID-19 vaccinations during the trial?
Prohibited and Concomitant Medications
3.5. What happens if the participant requires prohibited medication during the trial, can this participant continue in the study?
3.6. Should study medication stop if erythromycin is required?
3.7. Can the participant stop aspirin during the trial?
3.8. Is anticoagulant medication for dialysis patients permitted in this trial?
3.9. Does the dose of heparin need to be reduced during haemodialysis?
Other Special Scenarios
3.10. If the participant develops DVT/PE and requires anticoagulant prophylaxis for 6 months duration, study medication will be interrupted during this period. Can the study medication restart after 6 months?
3.11. If thrombosis occurs at the site of the catheter, how should this be managed?
3.12. Protocol Section 13.9 states that if the participant is within a 4.5hour window of ischemic stroke symptom onset, clinicians may choose to unblind to determine appropriateness of starting thrombolysis. If participant received placebo, participant can start on thrombolysis treatment immediately. However, if participant received rivaroxaban, there are concerns that thrombolysis treatment cannot be given and potentially there will be complaints from the participant. If the participant has an acute MI/stroke and requires urgent thrombolysis, do we need to unblind as well?
3.13. What happens if the participant has a stroke or acute coronary syndrome?
3.14. What happens if a participant is found to have lacunar stroke after they have been included in the study?
3.15. What happens if the participant requires an epidural anaesthetic?
3.16. What happens if the participant requires a procedure such as haemodialysis catheter insertion?
3.17. What happens if the participant requires emergency surgery?
3.18. What is the guidance for withholding study medication prior to procedures?
3.19. If a participant undergoes a kidney transplant, should study medication stop?
3.20. What happens if the participant has Acute Kidney Injury?
3.1. Are blood tests and/or ECGs required during the trial?
TRACK is a pragmatic trial and no laboratory tests are required during follow-up.
3.2. Is laboratory monitoring with coagulation tests required during the trial?
Laboratory monitoring with coagulation tests is not required and not recommended.
3.3. Is there any difference between rivaroxaban and aspirin in terms of bleeding risk?
There are no data on the bleeding risk of low dose rivaroxaban in patients with advanced CKD, including those on dialysis. The results of the COMPASS trial showed that, in the subgroup of patients with CKD (eGFR 15-59 mL/min/1.73m2) the net-clinical benefit outcome (a composite of efficacy and bleeding outcomes) was in favour of the combination of low dose rivaroxaban and aspirin compared with aspirin alone.
3.4. Can participants have COVID-19 vaccinations during the trial?
Yes, COVID-19 vaccination is encouraged.
3.5. What happens if the participant requires prohibited medication during the trial, can this participant continue in the study?
The study medication must be stopped in participants who require prohibited medication during the study. Do not combine prohibited medication with study medication. Participants should continue in the study and continue with study visits even if the study medication is stopped so that follow-up data can be collected. If prohibited medication treatment is no longer required, the study medication can be re-started if medically safe, at the discretion of the treating physician.
3.6. Should study medication stop if erythromycin is required?
The study medication must be stopped in participants who require erythromycin. If erythromycin is no longer required, the study medication can be re-started.
3.7. Can the participant stop aspirin during the trial?
Use of aspirin is at the discretion of the treating physician. Please record aspirin use in the Concomitant Medications eCRF.
3.8. Is anticoagulant medication for dialysis patients permitted in this trial?
Usual anticoagulant medication for dialysis can be continued during the trial. Patients can continue to use the same dose throughout the trial.
3.9. Does the dose of heparin need to be reduced during haemodialysis?
There is no need to reduce the dose of heparin if it is used during haemodialysis for regional anticoagulation. The use of unfractionated heparin, LMWH, direct thrombin inhibitors, or fondaparinux during haemodialysis for regional anticoagulation will be allowed at the same dose as usual – see Section 13.13.3 of protocol.
Other Special Scenarios
3.10. If the participant develops DVT/PE and requires anticoagulant prophylaxis for 6 months duration, study medication will be interrupted during this period. Can the study medication restart after 6 months?
Yes, participants can re-start study medication after 6 months. Study medication should not be restarted until at least 12 hours after last administration of any anticoagulant. See section 13.13.3 of protocol “Concurrent use of anticoagulation” or TRACKtrial website: https://www.tracktrial.org/clinical-guidance-for-special-scenarios/
3.11. If thrombosis occurs at the site of the catheter, how should this be managed?
Treat the thrombosis at the catheter site as per usual practice. There is no need to stop the study medication if systemic anticoagulation or thrombolysis is not required.
3.12. Protocol Section 13.9 states that if the participant is within a 4.5hour window of ischemic stroke symptom onset, clinicians may choose to unblind to determine appropriateness of starting thrombolysis. If participant received placebo, participant can start on thrombolysis treatment immediately. However, if participant received rivaroxaban, there are concerns that thrombolysis treatment cannot be given and potentially there will be complaints from the participant. If the participant has an acute MI/stroke and requires urgent thrombolysis, do we need to unblind as well?
If a patient requires thrombolysis for stroke or MI, the PI can choose to unblind. The AHA Guidelines for the Early Management of Patients with Acute Ischemic Stroke recommend that recombinant tissue-type plasminogen activator should not be administered to people who take NOACs unless sensitive laboratory tests are normal or the patient has not received a dose of these agents for >48 hours. It should be noted that this guidance applies to only those taking a full dose of rivaroxaban (i.e. intended for therapeutic anticoagulation).
There are no official guidelines on the appropriateness of thrombolysis in patients who are taking a small dose of rivaroxaban. In clinical practice, thrombolysis is allowed for patients taking warfarin, but have INR <1.7. In TRACK, since the rivaroxaban dose is not intended for therapeutic anticoagulation (it is only one third of that required for therapeutic anticoagulation in non-dialysis patients and only half of that required for therapeutic anticoagulation in dialysis patients), thrombolysis could be considered on a case-by-case basis if other factors associated with increased risk of haemorrhage are absent.
For MI, the risks of bleeding are likely lower than that for stroke (for example, in case of stroke, the risk of haemorrhagic transformation of infract needs to be considered). Hence, it might be appropriate to thrombolysis for MI. Physicians should use their clinical judgement in making these decisions. If patient requires clot retrieval or coronary angiogram/angioplasty, unblinding is not required.
3.13. What happens if the participant has a stroke or acute coronary syndrome?
Treat participant as you would normally and stop study medication as required.
3.14. What happens if a participant is found to have lacunar stroke after they have been included in the study?
If you become aware during the trial that the participant had a lacunar stroke, the participant should stay in the study, stop taking the study medication and continue study follow-up as usual.
3.15. What happens if the participant requires an epidural anaesthetic?
Study medication needs to stop at least 60 hours before the epidural. If a catheter is in place, wait 24 hours after the catheter is removed before re-starting study medication.
3.16. What happens if the participant requires a procedure such as haemodialysis catheter insertion?
Please refer to Section 13 of the protocol (Clinical Guideline for Various Clinical Scenarios). If the procedure requires insertion of haemodialysis catheters, the study medication should be stopped 36 to 48 hours before the haemodialysis catheter insertion. In case of emergency, a dialysis catheter can be inserted at any time with close monitoring for bleeding complications.
3.17. What happens if the participant requires emergency surgery?
Please refer to Section 13.2.2 of the protocol “Guidance for the management of participants requiring emergency invasive procedure or surgical intervention”.
3.18. What is the guidance for withholding study medication prior to procedures?
Guidance about withholding study medication prior to procedures is in Section 13 of the protocol and on the TRACKtrial website https://www.tracktrial.org/clinical-guidance-for-special-scenarios/.
3.19. If a participant undergoes a kidney transplant, should study medication stop?
Yes, study medication must be stopped.
3.20. What happens if the participant has Acute Kidney Injury?
There is no need to stop the study medication for acute kidney injury per se. However, temporary discontinuation may be necessary if the participant develops an illness or condition where continuation of the study medication may not be in the participant’s best interest or they require administration of a prohibited medication (refer to Section 13.1 of the protocol).
4.1. Does this trial have a washout period?
The run-in phase (14 to 30 days) is designed to serve as a washout period.
4.2. Can telephone visits be replaced with on-site visits if the visit coincides with the participant’s appointment (i.e. dialysis appointment) at site?
This is acceptable as long as the required study assessments are performed.
4.3. What happens if the participant misses a few doses of study medication during the study period? Will the participant continue in the study?
Participants should note down the dates when study medication was missed and be reminded to adhere to the study medication regimen. The participant should remain in the study. Encourage the participant to continue in the study even if doses are missed or study medication is stopped. Whenever possible, restart the study medication.
4.4. How is the participant’s condition and study medication compliance evaluated between the 6-month clinic visits?
There are telephone calls between the 6-month clinic visits. Encourage the participant to adhere to the study medication regimen throughout follow-up. We can accurately determine the balance between the benefits and harms of low dose rivaroxaban in patients with CKD if more participants adhere to their study medication.
5.1. Is prolonged bleeding from a fistula site a study outcome?
This is only a study outcome if it leads to hospitalisation.
5.2. What happen if a participant experiences a trial outcome?
Trial follow-up should continue after a participant experiences a trial outcome. Some participants may need to stop the study medication.
5.3. Is angioplasty of dialysis AV fistula or AV graft a trial outcome?
Angioplasty of dialysis AV fistula or AV graft is not a trial outcome. If the procedure note mentions the presence of a thrombus (either occlusive or non-occlusive), this would be a trial outcome and the thrombus should be reported as a ‘thrombosis of dialysis access’ outcome.
6.1. When should emergency unblinding occur?
Emergency unblinding should only be undertaken when the knowledge of the study medication will influence the participant’s clinical management in a significant fashion. In most situations, temporary discontinuation of the study medication will be sufficient to manage the clinical problem. Refer to the Emergency Unblinding Procedure for more details.
6.2. Which are the most common potential side effects/adverse events from rivaroxaban?
The known risks of rivaroxaban are mainly around the bleeding risk from blood thinning agents. Side effects other than bleeding are very rare – seen in up to 1 in 1000 (<0.1%) of patients. These include hypersensitivity reactions and abnormal LFT.
Bleeding events are expected adverse events of rivaroxaban and should be reported on the Outcome eCRF. They do not require expedited reporting.
6.3. Are Suspected Unexpected Serious Adverse Reactions (SUSARs) expected in this trial?
SUSARs are not expected to occur. Site staff/Investigators should contact the National Lead or Chief Investigators if they suspect an event is a SUSAR.
6.4. What is the reporting timeframe for non-expedited SAEs (SAEs that are not SUSARs and are not of particular concern)? Is source documentation required?
Reporting of non-expedited SAEs is within 7 days of discharge from hospital. If the site does not become aware of the SAE until after discharge, SAE should be reported within 7 days of becoming aware. Minimal information will be required from sites for all non-expedited SAE reporting and except for study outcomes, source documentation is not required.
6.5. Does pneumonia need to be reported within 24 hours?
No, infections are common in CKD participants. Infections such as pneumonia are consistent with the natural history of advanced CKD/Kidney failure and associated conditions and should be reported within 7 days of discharge from hospital.
6.6. Do study outcomes like myocardial infarction, stroke and death need to be reported within 24 hours?
Study outcomes do not need to be reported within 24 hours. Outcomes are to be reported within 7 days of discharge from hospital.
6.7. If participant is a male and his partner becomes pregnant, does the pregnancy need to be followed up? Should the participant continue taking study medication?
Yes. Foetal/neonatal and maternal outcome at the end of the pregnancy must be followed-up (see section 9.8 of Manual of Operations). Sites only need to report the outcome of the pregnancy and any maternal or neonatal deaths, including miscarriages. The female pregnant partner does not need to go to the clinic for review. The participant should continue taking the study medication.
7.1. Can both study medication tablets be taken at once each day?
Study medication must be taken twice daily as terminal elimination half-life is ~8-9h and it is not dialysed. Participants cannot take both tablets at the same time.
7.2. Can sites dispense a monthly supply of study medication to participants?
A 6-month supply is dispensed to coincide with clinic visits. Pharmacy can dispense a 6-month supply and only give participants a 2-month supply. Each bottle contains a 2-month supply.
7.3. Can sites receive less than a 6-month supply of study medication if there are issues with space to store the IMP?
Smaller quantities can be shipped to sites if required.
7.4. Are there any instructions on how to perform tablet counts?
Sites should perform tablet counts as per local procedures. Tablet counts are only used to assess medication adherence.
7.5. What should be done with run-in medication after tablet counts?
Run-in medication can be destroyed after tablet counts and following email authorisation of destruction from the Regional Coordinating Centre.
7.6. When should the participant start taking study medication following dispensing at the screening and randomisation visits? Should the participant continue to take run-in study medication prior to arriving at site for the randomisation visit?
Participants should start taking run-in study medication on the same day as the screening visit. This is the commencement date of the run-in-phase. The run-in-phase lasts between 14 days and 30 days. Participants should continue to take the run-in medication until the morning of the randomisation visit. During the randomisation visit, new blinded study medication will be dispensed. Participants should start taking the newly dispensed study medication on the same day as the randomisation visit.
7.7. Should study medication be taken before or after dialysis?
Since rivaroxaban is not removed by dialysis, it does not matter whether the study medication is taken before or after haemodialysis.
