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

• ClinicalTrials.gov Identifier: NCT03969953
• Recruitment Status: Not yet recruiting
• First Posted: May 31, 2019
• Last Update Posted: March 11, 2020
• Sponsor: The George Institute
• Collaborators: George Clinical Pty Ltd; Bayer
• Information provided by (Responsible Party): The George Institute

Study Description

Brief Summary:

The TRACK trial is an investigator-initiated, multicentre, prospective, randomised, double-blind, 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 End Stage Kidney Disease (ESKD), and elevated cardiovascular (CV) risk, whilst maintaining an acceptable bleeding risk.

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Diseases; End-Stage Kidney Disease; Cardiovascular Disease	Drug: Rivaroxaban 2.5 Mg Oral Tablet; Other: Placebo	Phase 3

Detailed Description:

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-dependant End Stage Kidney Disease (ESKD) are sparse. Risk of bleeding in CKD and ESKD 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, although 90% of the trials evaluating these, exclude patients with CKD and ESKD, to mitigate trial risks.

The TRACK trial will evaluate the effect of low dose rivaroxaban in patients with CKD and ESKD. 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 ESKD, and elevated cardiovascular (CV) risk, with an acceptable bleeding risk.

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 ESKD, and an elevated CV risk.

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, double-blind, 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 2000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The TRACK trial is an investigator-initiated, multicentre, prospective, randomised, double-blind, 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-blind, Placebo-controlled
• Primary Purpose: Treatment
• Official Title: Treatment of Cardiovascular Disease With Low Dose Rivaroxaban in Advanced Chronic Kidney Disease
• Estimated Study Start Date: May 2020
• Estimated Primary Completion Date: December 2025
• Estimated Study Completion Date: December 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Rivaroxaban; Rivaroxaban 2.5mg, twice daily.	Drug: Rivaroxaban 2.5 Mg Oral Tablet; Rivaroxaban is an orally administered selective direct factor Xa inhibitor.; Other Name: Xarelto
Placebo Comparator: Placebo; Matched placebo, twice daily.	Other: Placebo; Rivaroxaban matched placebo

Outcome Measures

Primary Outcome Measures :

1. Risk of Major Adverse Cardiac Event (MACE) [ Time Frame: 5 years or trial closure ]

   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

Secondary Outcome Measures :

1. Composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke. [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, changes the risk of a composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke.
2. Composite outcome of all-cause death, non-fatal myocardial infarction, stroke, or PAD events. [ Time Frame: 5 years or trial closure ]
   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.
3. Composite outcome of all-cause death, non-fatal myocardial infarction, or stroke. [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, changes the risk of a composite of all-cause death, non-fatal myocardial infarction, or stroke.
4. Incidence of Cardiovascular Death [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, changes the risk of Cardiovascular Death
5. Incidence of Non-Fatal Myocardial Infarction [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, changes the risk of Non-Fatal Myocardial Infarction
6. Incidence of Stroke [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, changes the risk of Stroke
7. Incidence of PAD Events [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, changes the risk of PAD events
8. Net Clinical Benefit - incidence of MACE & Bleeding [ Time Frame: 5 years or trial closure ]
   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.
9. Incidence of Venous Thromboembolism [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, changes the risk of Venous Thromboembolism

Other Outcome Measures:

1. Cost Effectiveness of Intervention - Cost of intervention, & Net benefit in time to MACE event in intervention, when compared to placebo. [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, is cost effective. Where the primary outcome is positive, the cost of providing the intervention will be assessed against the MACE benefit achieved to determine if the treatment meets regulatory guidelines for cost effectiveness. E.g of the Australian Pharmaceutical Benefits Scheme (PBS).
2. Incidence of Thrombosis of dialysis vascular access [ Time Frame: 5 years or trial closure ]
   To determine whether the intervention, compared to placebo, changes the risk of thrombosis of dialysis vascular access among participants with an arteriovenous fistula/graft.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

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

  1. Age ≥18 years,
  2. ESKD 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,
  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),
  13. Haemoglobin <90 g/L, or platelet count <100 x 109/L,
  14. Significant liver disease 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. Pregnancy or intention to become pregnant or breast-feeding,
  17. Inability to understand or comply with the requirements of the study.

Contacts and Locations

Contacts

Contact: Sunil Badve; +61 2 8052 4636; sbadve@georgeinstitute.org.au

Contact: Arlen Wilcox; +61 2 8052 4594; awilcox@georgeinstitute.org.au

Locations

France

Centre Hospitalier Régional Universitaire

Nancy, France

Contact: Patrick Rossignol

Sponsors and Collaborators

The George Institute

George Clinical Pty Ltd

Bayer

Investigators

• Study Chair: Sunil Badve; The George Institute
• Study Chair: Martin Gallagher; The George Institute

More Information

Additional Information:

Trial Website 

• Responsible Party: The George Institute
• ClinicalTrials.gov Identifier: NCT03969953
• Other Study ID Numbers: 0040139
• First Posted: May 31, 2019
• Last Update Posted: March 11, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

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.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: To be confirmed

Access Criteria

• 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.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by The George Institute:

Rivaroxaban

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Cardiovascular Diseases; Urologic Diseases; Renal Insufficiency; Rivaroxaban; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anticoagulants