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

Phase 3

Recruiting

• Conditions: Dialysis-dependent Kidney Failure; Cardiovascular Disease; Chronic Kidney Diseases
• Interventions: Other: Placebo; Drug: Rivaroxaban 2.5 Mg Oral Tablet

• Registration Number: NCT03969953
• Lead Sponsor: The George Institute

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2019-05-27
• Study First Submitted QC: 2019-05-29
• Study First Posted: 2019-05-31
• Study Start: 2020-12-14
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-26
• Last Update Posted: 2023-11-28
• Primary Completion: 2027-06-30
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 2000

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Matched placebo, twice daily.
Rivaroxaban	Rivaroxaban 2.5 Mg Oral Tablet	Rivaroxaban 2.5mg, twice daily.

Primary Outcome Measures

Name	Time	Method
Risk of Major Adverse Cardiac Event (MACE)	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

Name	Time	Method
Incidence of Venous Thromboembolism	5 years or trial closure	To determine whether the intervention, compared to placebo, changes the risk of Venous Thromboembolism
Composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke.	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.
Incidence of Cardiovascular Death	5 years or trial closure	To determine whether the intervention, compared to placebo, changes the risk of Cardiovascular Death
Incidence of Non-Fatal Myocardial Infarction	5 years or trial closure	To determine whether the intervention, compared to placebo, changes the risk of Non-Fatal Myocardial Infarction
Composite outcome of all-cause death, non-fatal myocardial infarction, stroke, or PAD events.	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.
Composite outcome of all-cause death, non-fatal myocardial infarction, or stroke.	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.
Incidence of Stroke	5 years or trial closure	To determine whether the intervention, compared to placebo, changes the risk of Stroke
Incidence of PAD Events	5 years or trial closure	To determine whether the intervention, compared to placebo, changes the risk of PAD events
Net Clinical Benefit - incidence of MACE & Bleeding	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.

Trial Locations

Locations (82)

Hospital Canselor Tuanku Muhriz; 🇲🇾 Kuala Lumpur, Wilayah Persekutuan, Malaysia

Aysha Hospital; 🇮🇳 Chennai, Tamil Nadu, India

Centre Hospitalier Régional Universitaire de Nancy; 🇫🇷 Nancy, Meurthe-et-Moselle, France

Royal Adelaide Hospital; 🇦🇺 Adelaide, South Australia, Australia

Concord Repatriation General Hospital; 🇦🇺 Concord, New South Wales, Australia

Gold Coast University Hospital; 🇦🇺 Southport, Queensland, Australia

Royal North Shore Hospital; 🇦🇺 St Leonards, New South Wales, Australia

Logan Hospital; 🇦🇺 Meadowbrook, Queensland, Australia

St George Hospital; 🇦🇺 Kogarah, New South Wales, Australia

Wollongong Hospital; 🇦🇺 Wollongong, New South Wales, Australia

Nepean Hospital; 🇦🇺 Kingswood, New South Wales, Australia

Bendigo Health; 🇦🇺 Bendigo, Victoria, Australia

Ottawa Hospital Research Institute; 🇨🇦 Ottawa, Canada

CH Boulogne-sur-Mer, (CH Boulogne-sur-Mer); 🇫🇷 Boulogne-sur-Mer, France

Hôpital Ambroise Paré, (AP-HP); 🇫🇷 Boulogne-Billancourt, France

Noble Annex Hospital; 🇮🇳 Hadapsar, Pune Maharashtra, India

All India Institute Of Medical Sciences, Raipur; 🇮🇳 Raipur, Chhattisgarh, India

AURAL Strasbourg, (AURAL Strasbourg); 🇫🇷 Strasbourg, France

Hospital Raja Permaisuri Bainun, Ipoh; 🇲🇾 Ipoh, Perak, Malaysia

Institute of Post-Graduate Medical Education and Research; 🇮🇳 Kolkata, India

Sooriya Hospital; 🇮🇳 Saligramam, India

Khoo Teck Puat Hospital; 🇸🇬 Singapore, Singapore

Fu-Jen Catholic University Hospital; 🇨🇳 Taishan, New Taipei City, Taiwan

Military Hospital; 🇹🇳 Tunis, Tunisia

Sahloul Hospital; 🇹🇳 Sousse, Tunisia

Hôpital de la Cavale Blanche, (CHU Brest); 🇫🇷 Brest, France

AURAL Colmar, (AURAL Colmar); 🇫🇷 Colmar, France

CH Haguenau, (CH Haguenau); 🇫🇷 Haguenau, France

ALURAD Buisson, (ALURAD Buisson); 🇫🇷 Limoges, France

CHU Dupuytren, (CHU Dupuytren); 🇫🇷 Limoges, France

CH Mulhouse, (CH Mulhouse); 🇫🇷 Mulhouse, France

Hôpital Edouard Herriot, (CHU Lyon); 🇫🇷 Lyon, France

Hôpital Pasteur, (CHU Nice); 🇫🇷 Nice, France

Hôpital Lyon Sud, (CHU Lyon); 🇫🇷 Pierre-Bénite, France

Hôpital Bretonneau, (CHRU Tours); 🇫🇷 Tours, France

Prince of Wales Hospital; 🇦🇺 Randwick, New South Wales, Australia

Sunshine Hospital; 🇦🇺 St Albans, Victoria, Australia

Research St. Joseph's - Hamilton; 🇨🇦 Hamilton, Canada

Armadale Hospital; 🇦🇺 Armadale, Western Australia, Australia

Hôpital de Mercy, (CH Metz-Thionville); 🇫🇷 Ars-Laquenexy, France

AURAL Haguenau, (AURAL Haguenau); 🇫🇷 Haguenau, France

Hôpital de la Conception, (AP-HM); 🇫🇷 Marseille, France

AURAL Mulhouse, (AURAL Mulhouse); 🇫🇷 Mulhouse, France

Hôpital de la Maison Blanche, (CHU Reims); 🇫🇷 Reims, France

Hôpitaux de Brbaois, (ALTIR); 🇫🇷 Vandœuvre-lès-Nancy, France

Kasturba Medical College and Hospital, Manipal; 🇮🇳 Udupi, Karnataka, India

Muljibhai Patel Urological Hospital; 🇮🇳 Nadiād, Gujarat, India

All India Institute of Medical Sciences, Bathinda; 🇮🇳 Bathinda, Punjab, India

Postgraduate Institute of Medical Education and Research, Chandigarh; 🇮🇳 Chandigarh, India

KG Hospital, K.Govindaswamy Naidu Medical Trust; 🇮🇳 Coimbatore, India

L & T Prayas Medical Centre; 🇮🇳 Virugambakkam, India

Hospital Sultanah Bahiyah; 🇲🇾 Alor Setar, Kedah, Malaysia

Hospital Raja Perempuan Zainab II; 🇲🇾 Kota Bharu, Kelantan, Malaysia

Hospital Seberang Jaya; 🇲🇾 Seberang Jaya, Penang, Malaysia

Hospital Tuanku Ja'afar, Seremban; 🇲🇾 Seremban, Negeri Sembilan, Malaysia

Hospital Queen Elizabeth, Kota Kinabalu; 🇲🇾 Kota Kinabalu, Sabah, Malaysia

Hospital Kajang; 🇲🇾 Kajang, Selangor, Malaysia

University of Malaya Medical Centre; 🇲🇾 Kuala Lumpur, Wilayah Persekutuan, Malaysia

Tan Tock Seng Hospital; 🇸🇬 Singapore, Singapore

Kaohsiung Medical University Chung-Ho Memorial Hospital; 🇨🇳 Kaohsiung, Taiwan

King Abdullah International Medical Research Center; 🇸🇦 Riyadh, Saudi Arabia

Kaohsiung Chang-Gung Memorial Hospital; 🇨🇳 Kaohsiung, Taiwan

Chung-Shan Medical University Hospital; 🇨🇳 Taichung, Taiwan

Wan fang Hospital; 🇨🇳 Taipei, Taiwan

Taipei Tzu Chi Hospital; 🇨🇳 Taipei, Taiwan

Chang Gung Memorial Hospital, Linkou Medical Center; 🇨🇳 Taoyuan, Taiwan

Mongi Slim Hospital; 🇹🇳 Tunis, Tunisia

Canberra Hospital; 🇦🇺 Garran, Australian Capital Territory, Australia

VS Hospital; 🇮🇳 Kilpauk, India

Government Hospital; 🇮🇳 Proddatūr, India

Hemodialysis Care Project North Centre; 🇸🇦 Al-Yasmin, Riyadh, Saudi Arabia

Hemodialysis King Abdullah Centre; 🇸🇦 Al-Yasmin, Riyadh, Saudi Arabia

ialysis Centre - King Abdul Aziz Medical City (KAMC); 🇸🇦 Ar-Rimayah, Riyadh, Saudi Arabia

Aykai Super Speciality Hospital, Ludhiana; 🇮🇳 Ludhiāna, Punjab, India

Osmania General Hospital; 🇮🇳 Hyderabad, Telangana, India

Citizens Hospital; 🇮🇳 Hyderabad, Telangana, India

Nizam's Institute of Medical Sciences, Hyderabad; 🇮🇳 Hyderabad, Telangana, India

Fattouma Bourguiba Hospital; 🇹🇳 Monastir, Tunisia

Hedi chaker Hospital; 🇹🇳 Sfax, Tunisia

Charles Nicolle Hospital; 🇹🇳 Tunis, Tunisia

La Rabta Hospital; 🇹🇳 Tunis, Tunisia

Hemodialysis Care Project South Centre; 🇸🇦 Riyad, Riyadh, Saudi Arabia