Evaluation of Low-Dose Rivaroxaban for Cardiovascular Event Reduction in Patients with Advanced Chronic Kidney Disease or Dialysis Dependency

Trial ID: 2024-512483-59-00
Protocol: TRACK_001
Sponsor: The George Institute For Global Health

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Diseases & Conditions

Chronic kidney disease Dialysis

Objectives

The primary objective of this study is to evaluate whether low dose **rivaroxaban** (2.5 mg twice daily) significantly reduces the risk of a composite outcome of cardiovascular (CV) death, non-fatal myocardial infarction, stroke, or peripheral arterial disease events in patients with chronic kidney disease (CKD) stages 4 or 5, or those with dialysis-dependent kidney failure, who also have an elevated CV risk. This is clinically relevant as it addresses the high cardiovascular morbidity and mortality in this patient population, potentially offering a therapeutic strategy to mitigate these risks.

Secondary objectives include determining whether, in individuals with CKD stages 4 or 5 kidney failure or those on dialysis with elevated CV risk, low dose rivaroxaban compared to placebo reduces the risk of CV death, all-cause mortality, risk of individual components of composite outcomes, and risk of venous thromboembolism. These objectives aim to provide a comprehensive understanding of the potential benefits of rivaroxaban in reducing various cardiovascular and thromboembolic risks in this vulnerable population.

Participants

The clinical trial involves a total of **1550 participants** who are being studied to assess the improvement of cardiovascular outcomes in patients with advanced chronic kidney disease. The study population includes both **male and female** subjects, aged **18 years and older**, with a focus on individuals with chronic kidney disease stages 4 or 5, or those who are dialysis-dependent. Participants were selected based on their ability to provide informed consent and their elevated cardiovascular risk, which is defined by a history of coronary artery disease, peripheral arterial disease, non-haemorrhagic non-lacunar stroke, diabetes mellitus, or being aged 65 years or older. The trial does not include a vulnerable population. The participants' general health status is characterized by their advanced kidney disease and associated cardiovascular risk factors. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of low-dose **rivaroxaban** in improving cardiovascular outcomes in patients with advanced chronic kidney disease. This is a Phase III, randomized, double-blind, placebo-controlled trial. The trial aims to determine whether rivaroxaban 2.5 mg, administered twice daily, significantly reduces the risk of a composite outcome of cardiovascular death, non-fatal myocardial infarction, stroke, or peripheral arterial disease events in patients with chronic kidney disease stages 4 or 5, or those with dialysis-dependent kidney failure and elevated cardiovascular risk. The trial is expected to run from March 2023 to March 2026, with an estimated duration of 78 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (≥18 years), kidney failure status, and elevated cardiovascular risk. Following successful screening, participants will be randomized to receive either rivaroxaban or a matching placebo. Study visits will include regular follow-up assessments to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will conclude the participant's involvement, during which final evaluations will be conducted to assess the primary and secondary endpoints.

The expected length of participant involvement is approximately 78 weeks, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The primary endpoints include cardiovascular death, non-fatal myocardial infarction, stroke, or peripheral arterial disease events, while secondary endpoints encompass a range of cardiovascular and mortality outcomes. The trial is not classified as low intervention and is conducted under the sponsorship of Bayer Healthcare AG, with rivaroxaban being the investigational product.

Treatment

The clinical trial involves the administration of **Rivaroxaban**, an experimental medication, in the form of a 2.5 mg **film-coated tablet**. The active substance in this medication is **Rivaroxaban**, which is a chemical compound. The pharmaceutical form is designed for **oral use**. Participants in the trial will receive a dosage of 2.5 mg twice daily, with a maximum daily dose of 5 mg. The total maximum dose over the treatment period is 11.88 grams. The treatment period is set for a maximum of 78 weeks. The medication is manufactured by Bayer Healthcare AG and is identified by the product code PRD55496.

In addition to the experimental medication, a **matching placebo** is used in the study. The placebo is designed to mimic the appearance of the Rivaroxaban 2.5 mg film-coated tablets, ensuring blinding in the trial. The placebo is administered orally, following the same dosing schedule as the experimental medication, which is twice daily. The use of a placebo allows for a controlled comparison to assess the efficacy of Rivaroxaban in reducing cardiovascular events in patients with advanced chronic kidney disease.

Efficacy

Efficacy in the clinical trial titled "TRACK - Treatment of cardiovascular disease with low dose Rivaroxaban in Advanced CKD" will be assessed using both primary and secondary endpoints. The primary endpoints include the incidence of **cardiovascular (CV) death**, non-fatal myocardial infarction, stroke, or peripheral arterial disease (PAD) events. These endpoints are critical in evaluating the effectiveness of low-dose Rivaroxaban (2.5 mg twice daily) compared to placebo in reducing cardiovascular risks in patients with chronic kidney disease (CKD) stages 4 or 5, or those with dialysis-dependent kidney failure.

Secondary endpoints will further assess efficacy through a variety of measures, including the 3-point major adverse cardiovascular events (MACE), all-cause death, and composite outcomes such as all-cause death combined with non-fatal myocardial infarction or stroke. Additional secondary endpoints include the individual components of these composite outcomes, net-clinical-benefit outcomes, and the occurrence of venous thromboembolism. These parameters will provide a comprehensive evaluation of the treatment's impact on the patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

People able to provide informed consent who meet all of the following inclusion criteria, 2. Age ≥18 years, 3. 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, 4. Elevated CV risk, defined by at least one of the following: a. History of CAD or PAD or non-haemorrhagic non-lacunar stroke, OR b. Diabetes mellitus, OR c. Age ≥65 years.

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Exclusion Criteria

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 NYHA 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 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.