Clinical trial NCT03969953: Treatment of Cardiovascular Disease With Low Dose Rivaroxaban in Advanced Chronic Kidney Disease
Official title: Treatment of Cardiovascular Disease With Low Dose Rivaroxaban in Advanced Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Chronic Kidney Diseases
Dialysis-dependent Kidney Failure
Cardiovascular Disease
Keywords: Rivaroxaban
Lead sponsor: The George Institute
Sponsor class: OTHER
Collaborators: name: George Clinical Pty Ltd
name: Bayer
name: Central Hospital, Nancy, France
name: King Abdullah International Medical Research Center
First posted: 2019-05-31
Enrollment: 2000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Risk of Major Adverse Cardiac Event (MACE)
timeFrame: 5 years or trial closure
Secondary outcomes:
measure: Composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke.
timeFrame: 5 years or trial closure
measure: Composite outcome of all-cause death, non-fatal myocardial infarction, stroke, or PAD events.
timeFrame: 5 years or trial closure
measure: Composite outcome of all-cause death, non-fatal myocardial infarction, or stroke.
timeFrame: 5 years or trial closure
measure: Incidence of Cardiovascular Death
timeFrame: 5 years or trial closure
measure: Incidence of Non-Fatal Myocardial Infarction
timeFrame: 5 years or trial closure
measure: Incidence of Stroke
timeFrame: 5 years or trial closure
measure: Incidence of PAD Events
timeFrame: 5 years or trial closure
measure: Net Clinical Benefit - incidence of MACE & Bleeding
timeFrame: 5 years or trial closure
measure: Incidence of Venous Thromboembolism
timeFrame: 5 years or trial closure
Other outcomes:
measure: Cost Effectiveness of Intervention - Cost of intervention, & Net benefit in time to MACE event in intervention, when compared to placebo.
timeFrame: 5 years or trial closure
measure: Incidence of Thrombosis of dialysis vascular access
timeFrame: 5 years or trial closure
Locations:
city: Garran
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Meadowbrook
country: Australia
facility: Logan Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bendigo
country: Australia
facility: Bendigo Health
state: Victoria
city: St Albans
country: Australia
facility: Sunshine Hospital
state: Victoria
city: Armadale
country: Australia
facility: Armadale Hospital
state: Western Australia
city: Hamilton
country: Canada
facility: Research St. Joseph's - Hamilton
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
city: Nancy
country: France
facility: Centre Hospitalier Régional Universitaire de Nancy
state: Meurthe-et-Moselle
city: Ars-Laquenexy
country: France
facility: Hôpital de Mercy, (CH Metz-Thionville)
city: Boulogne-Billancourt
country: France
facility: Hôpital Ambroise Paré, (AP-HP)
city: Boulogne-sur-Mer
country: France
facility: CH Boulogne-sur-Mer, (CH Boulogne-sur-Mer)
city: Brest
country: France
facility: Hôpital de la Cavale Blanche, (CHU Brest)
city: Colmar
country: France
facility: AURAL Colmar, (AURAL Colmar)
city: Haguenau
country: France
facility: AURAL Haguenau, (AURAL Haguenau)
city: Haguenau
country: France
facility: CH Haguenau, (CH Haguenau)
city: Limoges
country: France
facility: ALURAD Buisson, (ALURAD Buisson)
city: Limoges
country: France
facility: CHU Dupuytren, (CHU Dupuytren)
city: Lyon
country: France
facility: Hôpital Edouard Herriot, (CHU Lyon)
city: Marseille
country: France
facility: Hôpital de la Conception, (AP-HM)
city: Mulhouse
country: France
facility: AURAL Mulhouse, (AURAL Mulhouse)
city: Mulhouse
country: France
facility: CH Mulhouse, (CH Mulhouse)
city: Nice
country: France
facility: Hôpital Pasteur, (CHU Nice)
city: Pierre-Bénite
country: France
facility: Hôpital Lyon Sud, (CHU Lyon)
city: Reims
country: France
facility: Hôpital de la Maison Blanche, (CHU Reims)
city: Strasbourg
country: France
facility: AURAL Strasbourg, (AURAL Strasbourg)
city: Tours
country: France
facility: Hôpital Bretonneau, (CHRU Tours)
city: Vandœuvre-lès-Nancy
country: France
facility: Hôpitaux de Brbaois, (ALTIR)
city: Raipur
country: India
facility: All India Institute Of Medical Sciences, Raipur
state: Chhattisgarh
city: Nadiād
country: India
facility: Muljibhai Patel Urological Hospital
state: Gujarat
city: Udupi
country: India
facility: Kasturba Medical College and Hospital, Manipal
state: Karnataka
city: Hadapsar
country: India
facility: Noble Annex Hospital
state: Pune Maharashtra
city: Bathinda
country: India
facility: All India Institute of Medical Sciences, Bathinda
state: Punjab
city: Ludhiāna
country: India
facility: Aykai Super Speciality Hospital, Ludhiana
state: Punjab
city: Chennai
country: India
facility: Aysha Hospital
state: Tamil Nadu
city: Hyderabad
country: India
facility: Osmania General Hospital
state: Telangana
city: Hyderabad
country: India
facility: Citizens Hospital
state: Telangana
city: Hyderabad
country: India
facility: Nizam's Institute of Medical Sciences, Hyderabad
state: Telangana
city: Chandigarh
country: India
facility: Postgraduate Institute of Medical Education and Research, Chandigarh
city: Coimbatore
country: India
facility: KG Hospital, K.Govindaswamy Naidu Medical Trust
city: Kilpauk
country: India
facility: VS Hospital
city: Kolkata
country: India
facility: Institute of Post-Graduate Medical Education and Research
city: Nandyāl
country: India
facility: Government Hospital
city: Proddatūr
country: India
facility: Government Hospital
city: Saligramam
country: India
facility: Sooriya Hospital
city: Virugambakkam
country: India
facility: L & T Prayas Medical Centre
city: Alor Setar
country: Malaysia
facility: Hospital Sultanah Bahiyah
state: Kedah
city: Kota Bharu
country: Malaysia
facility: Hospital Raja Perempuan Zainab II
state: Kelantan
city: Seremban
country: Malaysia
facility: Hospital Tuanku Ja'afar, Seremban
state: Negeri Sembilan
city: Seberang Jaya
country: Malaysia
facility: Hospital Seberang Jaya
state: Penang
city: Ipoh
country: Malaysia
facility: Hospital Raja Permaisuri Bainun, Ipoh
state: Perak
city: Kota Kinabalu
country: Malaysia
facility: Hospital Queen Elizabeth, Kota Kinabalu
state: Sabah
city: Kajang
country: Malaysia
facility: Hospital Kajang
state: Selangor
city: Kuala Lumpur
country: Malaysia
facility: Hospital Canselor Tuanku Muhriz
state: Wilayah Persekutuan
city: Kuala Lumpur
country: Malaysia
facility: University of Malaya Medical Centre
state: Wilayah Persekutuan
city: Al-Yasmin
country: Saudi Arabia
facility: Hemodialysis Care Project North Centre
state: Riyadh
city: Al-Yasmin
country: Saudi Arabia
facility: Hemodialysis King Abdullah Centre
state: Riyadh
city: Ar-Rimayah
country: Saudi Arabia
facility: ialysis Centre - King Abdul Aziz Medical City (KAMC)
state: Riyadh
city: Riyad
country: Saudi Arabia
facility: Hemodialysis Care Project South Centre
state: Riyadh
city: Riyadh
country: Saudi Arabia
facility: King Abdullah International Medical Research Center
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Singapore
country: Singapore
facility: Khoo Teck Puat Hospital
city: Taishan
country: Taiwan
facility: Fu-Jen Catholic University Hospital
state: New Taipei City
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chang-Gung Memorial Hospital
city: Taichung
country: Taiwan
facility: Chung-Shan Medical University Hospital
city: Taipei
country: Taiwan
facility: Wan fang Hospital
city: Taipei
country: Taiwan
facility: Taipei Tzu Chi Hospital
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital, Linkou Medical Center
city: Monastir
country: Tunisia
facility: Fattouma Bourguiba Hospital
city: Sfax
country: Tunisia
facility: Hedi chaker Hospital
city: Sousse
country: Tunisia
facility: Sahloul Hospital
city: Tunis
country: Tunisia
facility: Charles Nicolle Hospital
city: Tunis
country: Tunisia
facility: La Rabta Hospital
city: Tunis
country: Tunisia
facility: Military Hospital
city: Tunis
country: Tunisia
facility: Mongi Slim Hospital
Study officials:
affiliation: The George Institute
name: Sunil Badve
role: STUDY_CHAIR
affiliation: The George Institute
name: Martin Gallagher
role: STUDY_CHAIR
References: