The TRACK trial is an investigator-initiated, multicentre, prospective, randomised, quadruple-blind (participant, healthcare provider, data collector, outcomes assessor), placebo-controlled trial. TRACK is a global trial and will be conducted in renal units that provide comprehensive CKD care. Approximately 2000 participants will be recruited.

The TRACK trial will assess a strategy of administering low dose rivaroxaban to reduce the risk of major adverse cardiac event (MACE) in people with Chronic Kidney Disease (CKD) stages 4 or 5 or dialysis-dependent kidney failure, and elevated cardiovascular (CV) risk (marked by a history of CAD or PAD, or non-haemorrhagic non-lacunar stroke OR diabetes mellitus OR age ≥65 years).

Background and Rationale Chronic Kidney Disease (CKD) is a major international health burden. Despite the unacceptably high burden of cardiovascular disease (CVD) and associated mortality, trial-data on the management of CVD in people with advanced stages of CKD and dialysis-dependent kidney failure are sparse. Risk of bleeding in CKD and dialysis-dependent kidney failure is increased when compared to the general population. Anticoagulant agents, such as rivaroxaban, are a core intervention in the prevention of CVD in the general population. Nevertheless, to mitigate trial risks, 90% of the trials evaluating this form of intervention exclude these patient populations.

The TRACK trial will evaluate the effect of low dose rivaroxaban in patients with CKD dialysis-dependent kidney failure. Other trials have demonstrated that rivaroxaban reduces the risk of major cardio-vascular outcomes in high risk patients, and the limited data showed that CKD status did not significantly affect this result.

Hypothesis Compared to placebo, low dose rivaroxaban reduces the risk of major adverse cardiac event (MACE) in people with CKD stages 4 or 5 or dialysis-dependent kidney failure, and elevated cardiovascular (CV) risk (marked by a history of CAD or PAD, or non-haemorrhagic non-lacunar stroke OR diabetes mellitus OR age ≥65 years).

Objectives The primary objective is to determine whether low dose rivaroxaban, compared to placebo, significantly reduces the risk of a composite outcome of;

• CV death,
• non-fatal myocardial infarction,
• stroke, or
• peripheral artery disease (PAD) events

in people with CKD stages 4 or 5 or dialysis-dependent kidney failure, and an elevated CV risk (marked by a history of CAD or PAD, or non-haemorrhagic non-lacunar stroke OR diabetes mellitus OR age ≥65 years).

A full list of secondary objectives are detailed in the protocol, and include identifying risk reduction in the treatment group, and whether this treatment is cost effective.

Methodology The TRACK trial is an investigator-initiated, multicentre, prospective, randomised, quadruple-blind (participant, healthcare provider, data collector, outcomes assessor), placebo-controlled trial. The trial will test for the superiority of the trial intervention using a 1:1 allocation to parallel trial groups, on the basis of a pre-specified number of primary outcomes events.

This is a global trial and will be conducted in renal units that provide comprehensive CKD care. Approximately 2,000 participants will be recruited.

Inclusion Criteria:

• People able to provide informed consent who meet all of the following inclusion criteria:

  1. Age ≥18 years,

  2. Kidney Failure on haemodialysis or peritoneal dialysis, or CKD stage 4 or 5 (eGFR ≤29 mL/min/1.73 m2) not receiving renal replacement therapy,

  3. Elevated cardiovascular risk, defined by at least one of the following:

     1. History of Coronary Artery Disease (CAD) or PAD or non-haemorrhagic non-lacunar stroke, or
     2. Diabetes mellitus, or
     3. Age ≥65 years.

Exclusion Criteria:

• Potential participants must have none of the following exclusion criteria at the time of study enrolment:

  1. Mechanical/prosthetic heart valve (does not include bioprosthetic valves that do not require therapeutic anticoagulation),
  2. Indication for, or contraindication to, anticoagulant therapy,
  3. High bleeding risk including any coagulopathy,
  4. Lesion or condition considered to be a significant risk of major bleeding,
  5. Major bleeding episode in the 30 days prior to study enrolment, or any active and clinically significant bleeding,
  6. Current treatment with P2Y12 inhibitors/adenosine diphosphate (ADP) receptor inhibitors (clopidogrel, prasugrel, ticagrelor, cangrelor) or phosphodiesterase inhibitors (dipyridamole), where the treating physician or patient does not wish to stop these medications,
  7. Concurrent treatment with strong inhibitors of combined CYP3A4 and P-glycoprotein; or strong inducers of CYP3A4,
  8. Any stroke within 1 month prior to enrolment,
  9. Any previous history of a haemorrhagic or lacunar stroke,
  10. Severe heart failure with known ejection fraction <30% or New York Heart Association class III or IV symptoms,
  11. History of hypersensitivity or known contraindication to rivaroxaban,
  12. Uncontrolled hypertension (systolic BP ≥180 mm Hg or diastolic BP ≥110 mm Hg), at the time of screening
  13. Haemoglobin <90 g/L, or platelet count <100 x 109/L,
  14. Significant liver disease (defined as Child-Pugh Class B or C) or Alanine Aminotransferase (ALT) >3 times upper normal limit,
  15. Kidney transplant recipients with a functioning allograft, or scheduled for living-donor kidney transplant surgery,
  16. All countries except Europe: Pregnancy or intention to become pregnant or breast-feeding; Europe only: Women who are not in a postmenopausal state, where postmenopausal is defined as no menses for 12 months without alternative medical causes,
  17. Inability to understand or comply with the requirements of the study.

Trial data will be disseminated in the form of a publication to a relevant clinical journal and presentation at appropriate scientific conferences.

Individual participant data that underlie the results reported, after de-identification (text, tables, figures, and appendices), may be shared with Investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary") identified for this purpose.

To be confirmed

• No data should be released that would compromise the trial, unless specifically for safety reasons.
• There must be a strong scientific or other legitimate rationale for the data to be used for the requested purpose.
• TRACK Investigators should have a period of exclusivity in which to pursue their aims with the data, before key trial data are made available to other researchers.
• Adequate resources must be available in order to comply with the request, and the scientific aims of the study must justify the use of such resources.
• Data release complies with the relevant regulations from all relevant countries.

Quadruple-blind, Placebo-controlled