Treatment of Cardiovascular Disease With Low Dose Rivaroxaban in Advanced Chronic Kidney Disease

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Treatment of Cardiovascular Disease With Low Dose Rivaroxaban in Advanced Chronic Kidney Disease

Conditions
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Chronic Kidney Diseases, Dialysis-dependent Kidney Failure, Cardiovascular Disease

Intervention / Treatment
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* Drug: Rivaroxaban 2.5 Mg Oral Tablet
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: People able to provide informed consent who meet all of the following inclusion criteria: Age ≥18 years, 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, Elevated cardiovascular risk, defined by at least one of the following: History of Coronary Artery Disease (CAD) or PAD or non-haemorrhagic non-lacunar stroke, or Diabetes mellitus, or Age ≥65 years. Exclusion Criteria: Potential participants must have none of the following exclusion criteria at the time of study enrolment: Mechanical/prosthetic heart valve (does not include bioprosthetic valves that do not require therapeutic anticoagulation), Indication for, or contraindication to, anticoagulant therapy, High bleeding risk including any coagulopathy, Lesion or condition considered to be a significant risk of major bleeding, Major bleeding episode in the 30 days prior to study enrolment, or any active and clinically significant bleeding, 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, Concurrent treatment with strong inhibitors of combined CYP3A4 and P-glycoprotein; or strong inducers of CYP3A4, Any stroke within 1 month prior to enrolment, Any previous history of a haemorrhagic or lacunar stroke, Severe heart failure with known ejection fraction <30% or New York Heart Association class III or IV symptoms, History of hypersensitivity or known contraindication to rivaroxaban, Uncontrolled hypertension (systolic BP ≥180 mm Hg or diastolic BP ≥110 mm Hg), at the time of screening Haemoglobin <90 g/L, or platelet count <100 x 109/L, Significant liver disease (defined as Child-Pugh Class B or C) or Alanine Aminotransferase (ALT) >3 times upper normal limit, Kidney transplant recipients with a functioning allograft, or scheduled for living-donor kidney transplant surgery, 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, Inability to understand or comply with the requirements of the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rivaroxaban<br>Rivaroxaban 2.5mg, twice daily. | Drug: Rivaroxaban 2.5 Mg Oral Tablet<br>* Rivaroxaban is an orally administered selective direct factor Xa inhibitor.<br>* Other names: Xarelto;|
| Placebo Comparator: Placebo<br>Matched placebo, twice daily. | Other: Placebo<br>* Rivaroxaban matched placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Risk of Major Adverse Cardiac Event (MACE) | To determine whether the intervention, compared to placebo, changes the risk of a composite outcome of; CV death, non-fatal myocardial infarction, stroke, or peripheral artery disease (PAD) events | 5 years or trial closure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke. | To determine whether the intervention, compared to placebo, changes the risk of a composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke. | 5 years or trial closure | 
| Composite outcome of all-cause death, non-fatal myocardial infarction, stroke, or PAD events. | To determine whether the intervention, compared to placebo, changes the risk of a composite of all-cause death, non-fatal myocardial infarction, stroke, or PAD events. | 5 years or trial closure | 
| Composite outcome of all-cause death, non-fatal myocardial infarction, or stroke. | To determine whether the intervention, compared to placebo, changes the risk of a composite of all-cause death, non-fatal myocardial infarction, or stroke. | 5 years or trial closure | 
| Incidence of Cardiovascular Death | To determine whether the intervention, compared to placebo, changes the risk of Cardiovascular Death | 5 years or trial closure | 
| Incidence of Non-Fatal Myocardial Infarction | To determine whether the intervention, compared to placebo, changes the risk of Non-Fatal Myocardial Infarction | 5 years or trial closure | 
| Incidence of Stroke | To determine whether the intervention, compared to placebo, changes the risk of Stroke | 5 years or trial closure | 
| Incidence of PAD Events | To determine whether the intervention, compared to placebo, changes the risk of PAD events | 5 years or trial closure | 
| Net Clinical Benefit - incidence of MACE & Bleeding | To determine whether the intervention, compared to placebo, changes the risk of a composite outcome of cardiovascular death, non-fatal myocardial infarction, stroke, PAD events, fatal bleeding, or symptomatic bleeding into a critical organ. | 5 years or trial closure | 
| Incidence of Venous Thromboembolism | To determine whether the intervention, compared to placebo, changes the risk of Venous Thromboembolism | 5 years or trial closure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rivaroxaban