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Trial registered on ANZCTR


Registration number
ACTRN12616000736448
Ethics application status
Approved
Date submitted
1/06/2016
Date registered
3/06/2016
Date last updated
Type of registration
Prospectively registered

Titles & IDs
Public title
Canadian-Australian Randomised Trial of Screening Kidney Transplant Candidates for Coronary Artery Disease
Scientific title
Canadian-Australian Randomised Trial of Screening Kidney Transplant Candidates for Coronary Artery Disease
Secondary ID [1] 289143 0
Our Canadian partners are in the process of registering with CT.gov. We will update once registration number is known.
Universal Trial Number (UTN)
Trial acronym
CARSK study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Kidney failure 298649 0
Kidney transplant 298650 0
Coronary artery disease 298651 0
Condition category
Condition code
Renal and Urogenital 298714 298714 0 0
Kidney disease
Cardiovascular 298715 298715 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients randomised to no screening will not undergo regular non-invasive testing for CAD while on the kidney transplant wait list.

The current practice for wait list patients is to be screened every 1-2 years based on perceived risk of CAD. At any time, if patients develop symptoms of CAD, they will be treated according to local standard of care.

The duration of study is 4 years, with possible extension to 5 years for Canadian sites. Canadian transplant candidates typically wait longer than Australia/NZ candidates, hence the rationale for an extra year of follow up to capture patients who have been transplanted. Patients in this group will followed up 3 months and 12 months post-date of transplant. Transplanted patients will exit the study 12 months post-date of transplant.
Intervention code [1] 294658 0
Early detection / Screening
Comparator / control treatment
Patients randomised to routine screening will undergo noninvasive testing for coronary artery disease every year or second yearly as determined by local transplant centre practice. The duration of screening in the control is same as the intervention group (4-5 years depending on country).
Patients transplanted during the study will be followed for 12 months post-date of transplant and will exit study. This applies for both SCREENING and NO SCREENING groups.
Control group
Active

Outcomes
Primary outcome [1] 298192 0
Primary efficacy: major adverse cardiac event (MACE), defined as any of the following: cardiovascular death, myocardial infarction, emergency revascularisation, hospitalisation with unstable angina.

The outcome will be assessed by:
1) Notification to the transplant coordinators when patients are admitted in hospital (this is the usual standard of care in wait-listed patients).
2) The trial coordinator will gather electronic medical records, letters. procedure notes and will fill in the relevant case record form on the REDCap database (managed by Sydney local health district). All data are encrypted and stored on servers at SLHD, where it is backed up.
3) Patients will be followed up 6 monthly (alternating by phone and clinic visits) where trial coordinators will discuss any hospitalisations with the patients.
Timepoint [1] 298192 0
We will analyse time to MACE, within a 4 year study period (Australia and New Zealand) and 5-year study period (Canada)
Secondary outcome [1] 323451 0
All cause death
Timepoint [1] 323451 0
Such an event will be reported to the trial/coordinator at any stage during the 4-5 year study (this is already standard practice) and is usually instigated by patient's family, their nephrologists, general practitioners or cardiologists.

Trial coordinators will gather procedure notes/discharge letters and details will be entered into the REDCap database through relevant electronic case record forms (eCRFs).
Secondary outcome [2] 324441 0
Myocardial infarction
Timepoint [2] 324441 0
Such an event will be reported to the trial/coordinator at any stage during the 4-5 year study (this is already standard practice) and is usually instigated by patients, their nephrologists or cardiologists.

Trial coordinators will gather procedure notes/discharge letters and details will be entered into the REDCap database through relevant electronic case record forms (eCRFs).
Secondary outcome [3] 324442 0
Emergency revascularisation
Timepoint [3] 324442 0
Such an event will be reported to the trial/coordinator at any stage during the 4-5 year study (this is already standard practice) and is usually instigated by patients, their nephrologists or cardiologists.

Trial coordinators will gather procedure notes/discharge letters and details will be entered into the REDCap database through relevant electronic case record forms (eCRFs).
Secondary outcome [4] 324443 0
Stroke
Timepoint [4] 324443 0
Such an event will be reported to the trial/coordinator at any stage during the 4-5 year study (this is already standard practice) and is usually instigated by patients, their nephrologists or cardiologists.

Trial coordinators will gather procedure notes/discharge letters and details will be entered into the REDCap database through relevant electronic case record forms (eCRFs).
Secondary outcome [5] 324444 0
hospitalisation with arrhythmia
Timepoint [5] 324444 0
Such an event will be reported to the trial/coordinator at any stage during the 4-5 year study (this is already standard practice) and is usually instigated by patients, their nephrologists or cardiologists.

Trial coordinators will gather procedure notes/discharge letters and details will be entered into the REDCap database through relevant electronic case record forms (eCRFs).
Secondary outcome [6] 324445 0
major bleeding requiring hospitalisation
Timepoint [6] 324445 0
Such an event will be reported to the trial/coordinator at any stage during the 4-5 year study (this is already typically standard practice) and is usually instigated by patients, their nephrologists or cardiologists.

Trial coordinators will gather procedure notes/discharge letters and details will be entered into the REDCap database through relevant electronic case record forms (eCRFs).
Secondary outcome [7] 324446 0
Health related quality of life
Timepoint [7] 324446 0
Quality of life will be assessed at baseline, 6 months, 12 months, then 6 monthly thereafter for the duration of the study (4-5 years). We will administer two surveys: KDQOL-36 and EQ5D-5L. Both will be done at baseline, then this will be alternated in a 6 monthly interval.
Secondary outcome [8] 324447 0
Time off waiting list (including number of temporary suspension and duration of each suspension)
Timepoint [8] 324447 0
Trial coordinators will be notified by the transplant coordinators when patients are suspended from the wait list including dates of date suspension, and date of reactivation. Trial coordinators will then enter this information on the relevant eCRF. This outcome will be followed up throughout 4 years (in Australia/NZ) and up to 5 years in Canada.
Secondary outcome [9] 324448 0
Cost effectiveness
Timepoint [9] 324448 0
Data on resource use will be obtained in two ways. First through identification of tests, procedures and doctor’s visits related to cardiac and renal management for all study participants from randomisation to study end as recorded in the patient diaries and trial case report forms.
Second, Australian participants will have their records linked to the Admitted Patient Data Collection, Emergency Department Data Collection, and through Medicare for all Medicare Benefits Schedule (MBS) outpatient visits, procedures and the Pharmaceutical Benefits Scheme (PBS) for medicines.
The analysis will take place at the end of the study. This outcome will be followed up throughout 4 years (in Australia/NZ) and up to 5 years in Canada.
Secondary outcome [10] 324449 0
Incidence of permanent removal from list for cardiac causes
Timepoint [10] 324449 0
Trial coordinators will be notified by the transplant coordinators when patients are permanently removed from the wait-list and the reason for the removal. Trial coordinators will then enter this data onto relevant eCRF. This outcome will be followed up throughout 4 years (in Australia/NZ) and up to 5 years in Canada.
Secondary outcome [11] 324450 0
Incidence of transplantation
Timepoint [11] 324450 0
Such an event will be reported to the trial/coordinator at any stage during the 4-5 year study (this is already typically standard practice) and is usually instigated by patients, their nephrologists or cardiologists.

Trial coordinators will gather procedure notes/discharge letters and details will be entered into the REDCap database through relevant electronic case record forms (eCRFs).
Secondary outcome [12] 324451 0
Cancellation of transplant due to CAD
Timepoint [12] 324451 0
Such an event will be reported to the trial/coordinator at any stage during the 4-5 year study (this is already typically standard practice) and is usually instigated by patients, their nephrologists or cardiologists.

Trial coordinators will gather procedure notes/discharge letters and details will be entered into the REDCap database through relevant electronic case record forms (eCRFs).

Eligibility
Key inclusion criteria
1. adults aged 18 years of age or older who are active on the kidney transplant waiting list;
2. Dialysis-dependent kidney failure OR currently being assessed for OR active on the kidney transplant waiting list
3. expected to require further screening for CAD prior to transplantation (by current standard of care);
4. able to give consent;
5. anticipated to undergo transplantation more than 12 months from date of enrolment
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. patients with signs or symptoms suggestive of uncontrolled cardiac disease such as unstable coronary syndromes, decompensated heart failure, uncontrolled arrhythmia, and severe valvular heart disease;
2. patients who “on-hold” for transplantation due to a medical problem;
3. patients with other solid organ transplants;
4. multi-organ transplant candidates (e.g. kidney-pancreas transplant candidates);
5) patients with planned living donor transplant;
6) patients unable to give consent.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be web-based and managed by the Ottawa Hospital Research Institute, Methods Centre Data Management services.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation to treatment arm will be 1:1 allocation using random permuted blocks, stratified by site and diabetes status.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Multicentre, non-inferiority study
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Efficacy outcomes will be analysed using intention to treat. A significance level of 5% shall be used for all analyses, unless otherwise specified. All analyses will be adjusted for site.
The primary analysis will be an analysis of the time to first occurrence of the primary outcome MACE, using a Cox model with treatment arm as a covariate and stratified by site. This analysis will provide an estimate of the HR, a p-value and CI. Non-inferiority will be claimed if the 95%CI of the HR lies entirely lower than an HR value of 1.25, with the screening arm being the referent group. Superiority will be claimed if the 95%CI lies entirely lower than 1. Proportional hazards assumption will be assessed using log-log survival plots and Schoenfeld residuals.
The outcome of all-cause mortality will also be analyse using a Cox model. The time to all other outcomes will be analysed using a competing risk model, with the competing risk being death. Outcomes which can occur more than once will also be analysed using an Andersen and Gill model. This model is a natural extension of the Cox model and unlike the Poisson or Negative Binomial models for count data, does not require the assumption of a constant event rate over time. Robust standard errors using the Sandwich estimator will be applied to ensure the correct p-value and CIs are calculated.
All time to event data will also be graphically summarised using a Kaplan Meier or cumulative incidence curves comparing the two treatment arms.


Sample size calculation
We conservatively estimate an average MACE rate of 6%: MACE rates in the U.S. range from 8.7 % in the first year after a kidney transplant to 13.2 % per year on the waiting list. Using a MACE rate of 6% per year and non-inferiority defined as a Hazard Ratio (HR) of MACE < 1.25, randomization of 3306 patients will give us 80% power using a two-sided 5% significance level. An HR of 1.25 equates to an absolute difference in MACE being <1.4% higher in the non-screening group compared to the regular screening group (i.e. 7.4% versus 6.0 %).


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
14/06/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
3306
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,TAS,WA,VIC
Recruitment hospital [1] 5734 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 5735 0
Westmead Hospital - Westmead
Recruitment hospital [3] 5736 0
The Canberra Hospital - Garran
Recruitment hospital [4] 5737 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 5738 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [6] 5739 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [7] 5740 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 5741 0
Prince of Wales Hospital - Randwick
Recruitment hospital [9] 5742 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [10] 5898 0
Royal Hobart Hospital - Hobart
Recruitment outside Australia
Country [1] 7857 0
New Zealand
State/province [1] 7857 0
Auckland
Country [2] 7858 0
Canada
State/province [2] 7858 0
British Columbia

Funding & Sponsors
Funding source category [1] 293518 0
Government body
Name [1] 293518 0
National Health and Medical Research Council
Country [1] 293518 0
Australia
Funding source category [2] 293729 0
Charities/Societies/Foundations
Name [2] 293729 0
Heart Foundation
Country [2] 293729 0
New Zealand
Primary sponsor type
University
Name
University of Sydney
Address
Camperdown, Sydney, New South Wales 2006
Country
Australia
Secondary sponsor category [1] 292561 0
Individual
Name [1] 292561 0
John Gill
Address [1] 292561 0
St Paul's Hospital
Burrard St,
Vancouver, BC
Canada, V6Z 1Y6
Country [1] 292561 0
Canada
Secondary sponsor category [2] 292562 0
Individual
Name [2] 292562 0
Helen Pilmore
Address [2] 292562 0
Auckland City Hospital
Park Rd, Grafton, Auckland, New Zealand 1023
Country [2] 292562 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295011 0
Human Research Ethics Committee (Royal Prince Alfred Hospital)
Ethics committee address [1] 295011 0
Ethics committee country [1] 295011 0
Australia
Date submitted for ethics approval [1] 295011 0
Approval date [1] 295011 0
15/06/2015
Ethics approval number [1] 295011 0
Ethics committee name [2] 295172 0
Health and disability ethics committees
Ethics committee address [2] 295172 0
Ethics committee country [2] 295172 0
New Zealand
Date submitted for ethics approval [2] 295172 0
Approval date [2] 295172 0
29/09/2015
Ethics approval number [2] 295172 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 878 878 0 0
http://www.anzctr.org.au/AnzctrAttachments/370643-CARSKethics.pdf
Attachments [2] 918 918 0 0
http://www.anzctr.org.au/AnzctrAttachments/370643-CARSK protocol V3 02_05_aw_ty.docx

Contacts
Principal investigator
Name 65630 0
Prof Steven Chadban
Address 65630 0
Charles Perkins Centre
(2W73), level 2, Kidney node,
Building D17
Johns Hopkins Drive (off Missenden Road)
The University of Sydney NSW 2006
Country 65630 0
Australia
Phone 65630 0
+61295156600
Fax 65630 0
Email 65630 0
Steve.Chadban@sswahs.nsw.gov.au
Contact person for public queries
Name 65631 0
Tracey Ying
Address 65631 0
Charles Perkins Centre
(2W57), level 2, Kidney node,
Building D17
Johns Hopkins Drive (off Missenden Road)
The University of Sydney NSW 2006
Country 65631 0
Australia
Phone 65631 0
+61422336224
Fax 65631 0
Email 65631 0
tracey.ying@sswahs.nsw.gov.au
Contact person for scientific queries
Name 65632 0
Tracey Ying
Address 65632 0
Charles Perkins Centre
(2W57), level 2, Kidney node,
Building D17
Johns Hopkins Drive (off Missenden Road)
The University of Sydney NSW 2006
Country 65632 0
Australia
Phone 65632 0
+61422336224
Fax 65632 0
Email 65632 0
tracey.ying@sswahs.nsw.gov.au

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No Supporting Document Provided
Results publications and other study-related documents

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