Canadian-Australasian Randomised Trial of Screening Kidney Transplant Candidates for Coronary Artery Disease
Phase: NA
Conditions: Cardiovascular Diseases, End Stage Renal Disease, Kidney Transplantation, Dialysis Related Complication
Sponsor: University of British Columbia

 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 1 of 30 
CANADIAN-AUSTRALASIAN RANDOMISED TRIAL  
OF SCREENING KIDNEY TRANSPLANT CANDIDATES 
FOR CORONARY ARTERY DISEASE 
(CARSK STUDY) 
Protocol Number: 1 
Version: 5 
Date: 28/08/2018 
Version 1: 02/09/2015  
Version 2: 17/03/2016 
Version 3: 02/05/2016 
Version 4: 16/07/2016 
 
Author/s: 
Marcelo Cantarovich, Steve Chadban, Ben Chow, Matthew Kadatz, Phillip J. Devereaux, Jagbir Gill, 
John S. Gill, Patrick Kelly, S. Joseph Kim, Scott W. Klarenbach, Gregory Knoll, Rachael Morton, Helen 
Pilmore, Krishnan Ramanathan, Timothy Ramsay, Christine Ribic, Marcello Tonelli, Angela Webster, 
Tracey Ying. 
 
Clinical Events Committee Chair: Charles Herzog 
 
Sponsor/s: 
NHMRC Funded Clinical Trial Project grant #1084454 
 
 
Registration:  
ACTRN12616000736448 (www.anzctr.org.au) 
 
CONFIDENTIAL 
 
This document is confidential and the property of the investigators. No part of it may be transmitted, 
reproduced, published, or used without prior written authorization from the institution. 
 
Statement of Compliance 
 
This document is a protocol for a research project. This study will be conducted in compliance with 
all stipulation of this protocol, the conditions of the ethics committee approval, the NHMRC and 
CIHR National Statement on Ethical Conduct in Human Research (2007) updated May 2015 and 
March 2016 and the Note for Guidance on Good Clinical Practice (CPMP/ICH-135/95). 
 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 2 of 30 
TABLE OF CONTENTS 
CONTENTS 
Table of Contents ............................................................................................................................................................... 2 
1. Glossary of Abbreviations & Terms ........................................................................................................................ 4 
2. 
Study Sites ............................................................................................................................................................ 5 
2.1 
Study Location/s ......................................................................................................................................... 5 
3. 
Funding and Resources .................................................................................................................................... 8 
3.1 
Source/s of Funding ................................................................................................................................... 8 
4. 
Study Synopsis .................................................................................................................................................... 8 
4.1 
Background and rationale ....................................................................................................................... 8 
4.2 
Study design ................................................................................................................................................. 8 
4.3 
Study objectives .......................................................................................................................................... 8 
4.4 
Trial interventions ...................................................................................................................................... 8 
4.5 
Study population ........................................................................................................................................ 9 
4.6 
Study endpoints .......................................................................................................................................... 9 
4.7 
Study analyses ............................................................................................................................................. 9 
5. 
Introduction/Background Information ................................................................................................... 10 
5.1 
Lay Summary ............................................................................................................................................. 10 
5.2 
Background information ....................................................................................................................... 10 
6. 
Study Objectives .............................................................................................................................................. 15 
6.1 
Research Question .................................................................................................................................. 15 
6.2 
Outcome Measures ................................................................................................................................ 15 
7. 
Study Design ........................................................................................................................................................... 18 
7.1 
Study Design Diagram ............................................................................................................................ 18 
7.2 
Study Type &Design & Schedule ........................................................................................................ 18 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 3 of 30 
7.3 
Testing procedures ................................................................................................................................. 18 
7.4 
Standard Care and Additional to Standard Care Procedures .................................................... 21 
7.5 
Randomisation ......................................................................................................................................... 21 
7.6 
Economic methodology ................................................................................................................................. 21 
7.7 
Data Linkage ...................................................................................................................................................... 24 
8. 
Study Population ............................................................................................................................................. 24 
8.1 
Recruitment Procedure ......................................................................................................................... 24 
8.2 
Inclusion Criteria ...................................................................................................................................... 24 
8.3 
Exclusion Criteria ..................................................................................................................................... 25 
8.4 
Consent ....................................................................................................................................................... 25 
9. 
Participant Safety and Withdrawal ................................................................................................................ 25 
9.1 
Risk Management and Safety .............................................................................................................. 25 
9.2 
Handling of Withdrawals ...................................................................................................................... 25 
10. Statistical Methods ............................................................................................................................................... 25 
10.1 
Sample Size Estimation & Justification ............................................................................................. 25 
10.2 
Power Calculations.................................................................................................................................. 25 
10.3 
Statistical Methods To Be Undertaken ............................................................................................. 26 
11. Data Security & Handling ................................................................................................................................... 27 
11.1 
Details of where records will be kept & How long will they be stored .................................. 27 
11.2 
Confidentiality and Security ................................................................................................................. 28 
11.3 
Ancillary data ............................................................................................................................................ 28 
1. 
Appendix .................................................................................................................................................................. 28 
2. 
References ............................................................................................................................................................... 28 
 
 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 4 of 30 
1. GLOSSARY OF ABBREVIATIONS & TERMS 
Abbreviation 
Description (using lay language) 
CARSK 
Canadian-Australasian randomised trial of screening kidney 
transplant candidates for coronary artery disease 
CAD 
Coronary artery disease 
MACE 
Major adverse cardiac event 
ESKD 
End-stage kidney disease 
ANZDATA 
Australian and New Zealand 
QoL 
Quality of life 
PTCA 
Percutaneous transluminal coronary angiography 
CABG 
Coronary artery bypass grafting 
CK-MB 
Creatinine kinase 
SBP 
Systolic blood pressure 
BARC 
Bleeding Academic Research Consortium 
eCRF 
Electronic case report forms 
QALY 
Quality adjusted life years 
KMSA 
Kaplan Meier sample average 
IPW 
Inverse Probability Weighting 
MBS 
Medicare benefit schedule 
PBS 
Pharmaceutical benefits scheme 
AR-DRG 
Australian-refined Diagnosis related groups 
KDQOL-36 
Kidney disease quality of life instrument 
EQ5D-5L 
EuroQol – 5 Dimensions – 5 Levels 
REDCap 
Research electronic data capture 
SLHD 
Sydney local health district 

 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 5 of 30 
2. STUDY SITES 
2.1 STUDY LOCATION/S 
The study coordinating centre will be at C/O Dr Jagbir Gill, St Paul’s Hospital, Vancouver, BC. 
Site 
Site 
ID 
Address 
Contact 
Person 
Phone 
Email 
Royal Prince 
Alfred 
Hospital 
01 
Missenden 
Road, 
Camperdown 
NSW, Australia  
Steven 
Chadban 
+61295156600 
Steve.Chadban@sswahs.nsw.gov.
au 
Liverpool 
Hospital 
01 
Elizabeth St 
and Goulburn 
St, Liverpool, 
NSW, Australia 
Steve 
Chadban 
+61295156600 
Steve.Chadban@sswahs.nsw.gov.
au 
Westmead 
Hospital 
02 
Hawkesbury 
Road, 
Westmead 
NSW, Australia 
Angela 
Webster 
+61290369125 
angela.webster@sydney.edu.au 
Prince of 
Wales 
Hospital 
03 
Barker Street, 
Randwick 
NSW, Australia  
Paolo 
Ferrari 
+61293824447 
Paolo.ferrari@health.nsw.gov.au 
Canberra 
Hospital 
04 
Yamba Dr, 
Garran ACT 
2605 
Girish 
Taulikar 
+61262442046 
girish.talaulikar@act.gov.au 
Monash 
Medical 
Centre 
05 
Clayton Road, 
Clayton VIC, 
Australia 
John 
Kanellis 
+61395943529 
john.kanellis@monash.edu 
Royal 
Melbourne 
Hospital 
06 
Grattan Street, 
Parkville VIC, 
Australia 
Peter 
Hughes 
+61393423133 
peter.hughes@mh.org.au  
Austin 
Hospital 
07 
Studley Road, 
Heidelberg 
VIC, Australia 
Frank 
Ierino 
+61394965685 
Frank.IERINO@austin.org.au 
Box Hill 
08 
8 Arnold St, 
Box Hill, 
Darren Lee 
 
Darren.lee@easternhealth.org.au 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 6 of 30 
Hospital 
Victoria, 
Australia 
St George 
Hospital 
09 
Gray Street, 
Kogarah, NSW, 
Australia 
Sunil Badve 
+61293824447 
Sunil.Badve@health.nsw.gov.au 
Royal North 
Shore Hospital 
10 
Reserve Rd, St 
Leonards, 
NSW, Australia 
Stella 
McGinn 
+610299267111 
Stella.mcginn@health.nsw.gov.au 
Auckland City 
Hospital 
11 
Park Rd, 
Grafton, 
Auckland, New 
Zealand 
Helen 
Pilmore 
+6493797440 
HPilmore@adhb.govt.nz 
Christchurch 
Hospital 
12 
Riccarton 
Avenue, 
Christchurch, 
New Zealand 
Nick Cross 
+6403640655 
Nick.Cross@cdhb.health.nz 
Wellington 
Hospital 
13 
Riddiford St, 
Newtown, 
Wellington, 
New Zealand 
Murray 
Leikis 
+64048060637 
Murray.Leikis@ccdhb.org.nz 
Dunedin 
Hospital 
14 
Great King St, 
Dunedin, New 
Zealand 
John 
Schollum 
+64276009529 
john.schollum@southerndhb.gov
t.nz 
St Paul’s 
Hospital 
15 
Burrard St, 
Vancouver, 
BC, Canada 
Jagbir Gill 
604-682-2344 
Jagill@providencehealth.bc.ca 
Vancouver 
General 
Hospital 
16 
Laurel St, 
Vancouver, 
BC, Canada 
Olwyn 
Johnston 
604-875-4111 
Olwyn.Johnston@vch.ca 
University of 
Alberta 
17 
114 St/87 
Ave., 
Edmonton, AB, 
Canada 
Scott 
Klarenbach 
 
swk@ualberta.ca 
Health 
Sciences 
Centre, 
University of 
Manitoba 
18 
Winnipeg, MB, 
Canada 
David Rush 
 
 
drush@hsc.mb.ca 
 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 7 of 30 
University of 
Toronto UHN 
19 
Toronto, ON, 
Canada 
Sang 
Joseph Kim 
416-340-3228  
 
Joseph.Kim@uhn.ca  
 
St. Mike’s 
Hospital 
20 
Toronto, ON, 
Canada 
Jeff 
Zaltzman 
416-867-7444 
zaltmanj@smh.ca 
The Ottawa 
Hospital 
21 
Ottawa, ON, 
Canada 
Gregory 
knoll 
613-738-8400 
ext. 82536  
 
gknoll@ottawahospita.on.ca  
 
St. Joseph’s 
Healthcare 
22 
Hamilton, ON, 
Canada 
Christine 
Ribic 
905-522-1155 
ext. 33261  
 
christine.ribic@medportal.ca  
 
London 
Health 
Science 
Centre 
23 
London, ON, 
Canada 
Lakshman 
Gunaratma
n 
519-663-3632 
gunaratl@lhsc.on.ca 
McGill 
University 
Health Centre  
 
24 
Montréal, QC, 
Canada 
Marcelo 
Cantarovic
h 
 
514-934-1934 
ext. 36223 
marcelo.cantarovich@much.mcgi
ll.ca 
Queen 
Elizabeth II 
Health 
Sciences 
Centre 
25 
Halifax, NS, 
Canada 
Amanda 
Vinson 
902-473-4612 
amanda.vinson@nshealth.ca 
Universite de 
Montreal 
28 
Montreal, QC, 
Canada 
Duy Tran 
514-839-4464 
duypaul@icloud.com 

 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 8 of 30 
3. FUNDING AND RESOURCES 
3.1 SOURCE/S OF FUNDING 
Australia 
National Health Medical Research Council Funded Clinical Trial Project Grant 
#1084454 
New Zealand 
New Zealand Heart Foundation 
Canada 
Canadian Institutes of Health Research 
 
4. STUDY SYNOPSIS 
4.1 BACKGROUND AND RATIONALE 
Cardiovascular disease is the most common cause of death while on the kidney transplant waiting 
list and after transplantation. Current standard care involves screening for coronary artery disease 
prior to waitlist entry, then every 1-2 years, according to perceived risk, until transplanted. The aim 
of screening is two-fold. Firstly to identify patients with asymptomatic coronary disease to enable 
either correction, by bypass surgery or angioplasty, or removal of the patient from the list, with the 
ultimate aim of preventing premature cardiovascular mortality at the time of, or soon after kidney 
transplantation. Secondly, from a societal perspective, to prevent mis-direction of scarce donor 
organs into recipients who experience early mortality. This current screening strategy is not 
evidence based, has substantial known and potential harms, and is very costly. Two major issues of 
uncertainty require addressing in sequence: (1) whether to periodically screen asymptomatic wait-
listed patients for occult coronary artery disease; and (2) whether to revascularise coronary stenoses 
in asymptomatic patients prior to transplantation. The CARSK study seeks to address the first of 
these 2 issues. 
4.2 STUDY DESIGN 
CARSK is a multicentre, non-inferiority, 2-parallel-arm randomised trial. 
4.3 STUDY OBJECTIVES 
CARSK aims to 
1. Test the hypothesis that after screening for wait list entry, no further screening for coronary 
artery disease (CAD) is non-inferior to the current standard care which is screening all asymptomatic 
wait-listed patients for CAD at regular intervals. 
2. Compare the benefits and costs of not screening versus regular CAD screening from a health 
system perspective. 
4.4 TRIAL INTERVENTIONS 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 9 of 30 
People randomised to the intervention arm will receive no regular cardiac screening in the absence 
of symptoms of Coronary Artery Disease. 
People randomised to the control arm will receive routine coronary artery disease screening. 
Additionally all trial participants who develop symptoms or signs of cardiac disease will be 
investigated and treated as per local protocol. 
4.5 STUDY POPULATION 
We plan to enrol a total of 3,306 patients for the whole trial,1100 people on the kidney transplant 
waiting list in Australasia and 2206 inCanada. 
4.6 STUDY ENDPOINTS 
Primary efficacy endpoint: major adverse cardiac event (MACE), defined as any of the following: 
cardiovascular death, myocardial infarction, emergency revascularisation, hospitalisation with 
unstable angina. 
Primary safety endpoint; the above MACE endpoint plus complications from cardiac diagnosis or 
treatment including major bleeding requiring transfusions or hospitalizations, vascular intervention 
subsequent to cardiac interventions stroke and all-cause death. 
Secondary endpoints; death, cardiovascular death, procedure-related death, myocardial infarction, 
emergency revascularisation, stroke, hospitalisation with unstable angina, hospitalisation with heart 
failure, hospitalisation with arrhythmia, major bleeding, health-related quality of life (QoL), time off 
list (including number of temporary suspension and duration of each suspension), cost-effectiveness, 
incidence of permanent removal from list for cardiac causes; incidence of transplantation and 
cancellation of transplant due to CAD. 
4.7 STUDY ANALYSES 
Cox models will be used to assess the time to first MACE event and death. Competing risk models 
will be used to assess the time to all other outcomes, adjusting for death as the competing risk.  
 
 

 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 10 of 30 
5. INTRODUCTION/BACKGROUND INFORMATION 
5.1 LAY SUMMARY 
The CARSK trial will enrol people who are already on the kidney transplant waiting list, and who 
don’t have any symptoms of new heart problems. The patients enrolled will stay in the study for a 
maximum of 4 years in Australia and New Zealand and 5 years in Canada. While they are in the 
study, people will be followed up as usual – they will not have to have any extra appointments but 
will receive a 6-monthly phone call to check wait-list status and exclude any CAD events. They will 
also be asked to complete cost and quality of life questionnaires. The trial will use chance to allocate 
people to either getting no regular heart testing while they wait for a kidney transplant, or to get 
regular (every year or every second year) heart testing. We will make sure everyone gets tested if 
they develop any symptoms of heart problems. The trial will measure what happens to people, and 
particularly whether they develop any heart problems, whether they get a kidney transplant, and 
whether they have any heart problems after a transplant. The study is important as we know the 
most common cause of death for people on dialysis or after a transplant is heart related. We don’t 
know if finding heart disease and trying to treat it early, before it is bothering people, is a good idea 
– even though this is what is done at the moment. We think testing and treating people who don’t 
have symptoms might cause more problems than it solves -  it might remove them from the waiting 
list unnecessarily, or put them through tests and procedures or operations that they don’t really 
need, and waste a lot of peoples’ time and money without good reason. This CARSK study will help 
us work out whether regular testing is helpful, by showing us whether there is any difference to 
what happens to people if they are tested or not. The study investigators think it is likely that there 
will be no difference, so we have used best scientific principles to design the CARSK study to test 
whether we are right. 
5.2 BACKGROUND INFORMATION 
Kidney transplantation prolongs survival, improves quality of life, and is less costly than dialysis for 
people with end-stage kidney disease (ESKD).(1, 2)There are over 12,000 Australians, 2,600 New 
Zealanders and 20,000 Canadians who currently depend on dialysis for survival (3, 4). As quality of 
life and life expectancy are substantially improved by transplantation, the majority of these patients 
would like to receive a transplant. However, as only 800-1000 kidney transplants are performed 
annually, demand for transplantation far exceeds supply. Patients routinely wait on dialysis for an 
average of 2 to 7 years before they receive a deceased donor kidney transplant.(5, 6) The waiting list 
is dynamic, with new people joining, some being transplant, and others being removed temporarily 
or permanently. 
Wait-listed patients are at high risk for coronary artery disease (CAD) compared to the general 
population but are commonly asymptomatic. Exposure to dialysis is a major factor increasing the risk 
of cardiac events before and after transplantation.(7) Due to prolonged waiting times for a deceased 
donor kidney, the cardiac fitness of wait-listed patients must be maintained for long time periods. 
The risk of cardiac events and death in wait-listed patients is bi-modally distributed, being high 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 11 of 30 
whilst on dialysis, a transient increase immediately following transplantation in association with 
surgical stresses and high dose immunosuppression, then substantially reduced to a lower baseline 
after successful transplantation. (8, 9) The cumulative incidence of myocardial infarction ranges from 
8.7% to 16.7% by 3 years after wait-listing, and from 4.7% to 11.1% after 3 years of kidney 
transplantation.(10, 11) Cardiovascular disease is the most common cause of death in both wait-
listed patients and patients with a functioning transplant, accounting for 30% of mortality 
overall.(12) CAD is difficult to diagnose in ESKD patients who may not develop the classic symptoms 
of angina because of uraemia, physical limitations, diabetes, neuropathies and other factors. For 
example, among patients hospitalized with myocardial infarction, chest pain at presentation was less 
common in dialysis (44%) compared to non-dialysis patients (68%).(13) 
The average age and medical complexity of wait-listed patients is increasing. The proportion of 
transplant candidates 50 years and above increased by 62% between 1991 and 2011,(12) while the 
percentage with diabetes increased from 23% to 28% between 1998 and 2008.(14) Approximately 
15% of waitlisted patients, and 19% of those living with a functioning transplant are over 65 years.(6) 
Increasing age and co-morbidity substantially increases the risk of CAD. Changing donor 
characteristics are also likely to increase CAD risk after transplantation. In a bid to expand the donor 
pool and address the organ shortage, kidneys from ‘extended criteria’ donors (particularly older 
people with medical illnesses), are increasing in number (22% total donors in 2012). Recipients of 
these kidneys have more peri-operative complications, and a higher risk of peri-operative cardiac 
events, likely due to the higher incidence of delayed graft function (requirement for dialysis after 
transplantation) and related complications. The average donor age has increased by approximately 
0.5 years per annum for the past 10 years and was 49.7 years in 2012 – the highest on record. (15) 
Current CAD screening practice is not evidence based. Current transplant clinical practice guidelines 
recommend two phases of screening for CAD i) prior to acceptance onto the waiting list, and ii) 
screening at regular intervals (every 1-2 years) after wait-listing.(16) The aim of screening is to 
identify CAD by non-invasive tests (i.e. Exercise Stress test, Myocardial Perfusion Scintigraphy or 
Dobutamine Stress Echo or similar). Patients with abnormal non-invasive tests are typically removed 
from the waiting list and undergo coronary angiography followed by revascularization of any 
hemodynamically critical stenosis by coronary angioplasty with or without coronary stenting, or 
coronary artery bypass grafting. (16) Once the procedure is deemed successful and the patient 
recovered, they may be returned to the active transplant waiting list. Those with advanced, 
unmodifiable CAD are unlikely to have a survival benefit from transplantation and so are not listed, 
or if already on the list, are delisted. This strategy aims to promote survival peri-operatively and in 
the short-medium term after transplantation. From a societal perspective, it is also imperative to 
prevent mortality in the early post-transplant period as this also results in the loss of a donated 
kidney, which incurs an opportunity cost for those who remain on the waitinglist. 
Although regular, non-invasive cardiac screening is the current standard of care, only 1 randomized 
single centre trial performed in 1992 has ever been performed to evaluate this strategy. (17) This 
study recruited 26 insulin dependent diabetic transplant candidates with coronary artery stenoses 
greater than 75%, atypical or no chest pain, and a left ventricular ejection fraction greater than 35%, 
and randomised them to medical therapy (calcium channel blocker plus aspirin) or revascularization 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 12 of 30 
with angioplasty or coronary artery bypass grafting (CABG). Among the 13 patients assigned to 
medical therapy, 10 incurred a cardiac end point (including 4 deaths) compared to 2/13 
revascularised patients (p <0.01).(17) The study was prematurely terminated because of the 
imbalance of events between groups and slow recruitment. The applicability of this study is limited 
for several reasons: i) medical therapy has improved substantially ii) the study focused on a specific 
high-risk population (type 1 diabetics) who now represent <10% of the wait-listed population (18); 
iii) the study evaluated one time screening in an era when transplant waiting times were 
dramatically shorter; iv) the trial had few events overall hence the results have substantial fragility, 
and the trial was stopped early for a “too good to be true” treatment effect. 
The rationale for screening is challenged by observations that not all the excess cardiovascular 
disease burden of ESKD is related to CAD. ESKD patients most frequently die of sudden cardiac 
death, that may be arrhythmogenic in origin or may be related to uremic cardiomyopathy, and not 
atheromatous disease.(19) The rationale for screening for critical coronary stenoses also ignores 
evidence that the usual mechanism of myocardial infarction is atherosclerotic plaque rupture 
followed by thrombosis and occlusion of the affected coronary artery.(20) The risk of plaque rupture 
in the peri-operative period is related to tachycardia, increased sheer stress, and a hypercoagulable 
state.(21, 22) The most occlusive plaques are not necessarily prone to rupture and thrombosis.(23) 
One third of patients with peri-operative myocardial infarction sustain damage in areas distal to 
noncritical stenoses.(23) Finally, the available screening tests do not necessarily identify plaques at 
risk of rupture and thrombosis. 
Does routine screening have other downsides? Screening may paradoxically increase morbidity and 
mortality by: i) exposing patients to risk of angiography and revascularization procedures; or ii) by 
delaying or excluding patients from lifesaving kidney transplantation because of their perceived CAD 
status. In other settings, for example in most surgical candidates, screening is not beneficial. 
(24)However, the goals of screening transplant candidates differ somewhat from other settings, and 
include not only prevention of peri-operative cardiac events, but also maintenance of transplant 
eligibility during wait-listing, and long-term post-transplant survival. The current standard of care 
may be harmful. The potential harmful outcomes related to the current strategy of screening and 
revascularization of asymptomatic transplant candidates are summarized in Table 1 below. 
A recent joint Scientific Statement form the American Heart Association and the American College of 
Cardiology Foundation concluded “that there is no strong evidence for or against routine cardiac 
screening of asymptomatic transplant candidates” and that more evidence from randomized clinical 
trials was needed. (11) The lack of evidence in the transplant setting has led to confusion about the 
optimal management of transplant candidates: the two major issues of uncertainty are whether to 
screen asymptomatic patients for occult CAD, and whether to revascularise coronary stenoses in 
asymptomatic, screen-detected patients. 
 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 13 of 30 
 
Data to justify the focus on CAD screening tests only after people are wait listed The CARSK trial 
will focus on the use of screening tests after activation to the waiting list because Physicians are 
unwilling to forgo initial cardiac evaluation because these tests are considered essential to 
determine initial transplant eligibility. This assumption was proven by surveying current Canadian 
transplant centres: of 15 adult Transplant Centres, all centres screen for CAD during the initial 
transplant evaluation. Most (13/15) did not support randomization of patients to use or non-use of 
cardiac investigations during the initial evaluation of patients for activation onto the waiting list. In 
contrast, there is clinical equipoise around the use of screening tests for CAD after wait-listing: All 
centres reported screening for CAD after wait-listing. The majority of transplant centres (11/15) had 
a screening protocol, while in 4/15 centres transplant physicians individually selected patients for 
screening. The frequency of screening reported in hypothetical patient scenarios equalled or 
exceeded that recommended in current transplant guidelines.(18) All 15 centres were willing to 
randomize patients to regular or selective screening after wait-listing. The largest health services 
burden is related to screening practices after wait-listing (typically 2-7 years), rather than the one 
time testing prior to placement on the waiting list. 
Data to demonstrate screening for CAD is expensive. Our Canadian investigators studied costs in a 
pilot study and found, of 604 wait-listed patients in British Columbia followed for 3.7± 1.8 years, 530 
non-invasive cardiac screening tests with an estimated cost of over C$530,000 were required by 
current guidelines.(18) When the additional costs of program administration, coronary angiography, 
consultations and revascularization procedures in patients with abnormal screening tests were 
considered, the current non-evidence based strategy costs a minimum of $15 million per year in 
Canada.(25) The estimated cost of a single screening test for those wait listed in Australia is in excess 
of $1.1 million each year, and for the over 90,000 wait-listed patients in the United States is $210 
million.(26, 27) To date no studies have examined the cost-effectiveness of screening strategies for 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 14 of 30 
coronary artery disease. In order to ensure health care system sustainability and maximize patient 
outcomes given finite health care resources, it is critical that the effectiveness and cost-effectiveness 
of screening strategies be determined. 
Data to suggest selective screening may be safe in wait listed patients: The 604 wait listed 
Canadians in the above pilot study only underwent screening based on on-going clinical 
evaluation.(18) This strategy resulted in fewer screening tests than recommended by guidelines (n 
=171 versus 530 tests), and no difference in cardiovascular events (cardiovascular event rate in 
patients without the recommended frequency of cardiac tests was 6.7 [95% CI, 5.2 to 8.7] per 100 
patient-years, and in those screened regularly was 9.9 [95% CI, 7.1 to 13.7].(18) Two other 
observational studies also suggest that selective screening may be safe: in a single centre study of 
514 wait-listed candidates who were screened based on clinical judgment of the treating physician, 
the incidence of cardiac events at 5 years in the 224 patient who were not screened was 5.3% 
compared to 19.7% among the 290 patients who were screened. (28) Similarly, in another study of 
600 wait-listed patients, 174 patients were considered high risk based on clinical criteria and 
underwent screening for CAD and only 5 (2.9%) were revascularised. Cardiac events were higher in 
screened patients 12/174 (6.9%) versus unscreened patients 19/426 (4.5%).(29) Selection bias is 
likely in all these studies: only an RCT can answer the question definitively. The first phase will 
confirm protocol adherence, patient enrolment and consent rates of the 144 wait-listed participants 
who will be randomised to no screening versus routine screening for CAD, aiming to produce a 95% 
confidence interval equal to the sample adherence prevalence plus or minus 5% when the true 
prevalence of adherent patients is hypothesized to be 90%.  
 

 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 15 of 30 
6. STUDY OBJECTIVES 
6.1 RESEARCH QUESTION 
Using randomised controlled trial design, with participants wait listed for kidney transplantation we 
will 
 
test the hypothesis that not screening asymptomatic wait-listed kidney transplant candidates for 
coronary artery disease is non-inferior to serial screening at regular interval (i.e. annually) using 
non-invasive cardiac screening tests (i.e. myocardial perfusion scintigraphy or dobutamine stress 
echo) for the composite primary efficacy outcome of major adverse cardiac event (MACE) 
defined as cardiac death, non-fatal myocardial infarction, urgent coronary revascularization and 
hospitalization for unstable angina. 
 
 
compare the benefits and costs of screening and subsequent treatment at wait list entry versus 
regular CAD screening from a health system perspective. 
6.2 OUTCOME MEASURES 
Primary efficacy endpoint: major adverse cardiac event (MACE), defined as any of the following: 
cardiovascular death, myocardial infarction, emergency revascularisation, hospitalisation for 
unstable angina. 
Primary safety endpoint; the above MACE endpoint plus complications from cardiac diagnosis or 
treatment including major bleeding requiring transfusions or hospitalizations, vascular intervention 
subsequent to cardiac interventions stroke and all-cause death. 
Secondary endpoints; death, cardiovascular death, procedure-related death, myocardial infarction, 
emergency revascularisation, stroke, hospitalisation with unstable angina, hospitalisation with heart 
failure, hospitalisation with arrhythmia,  major bleeding, health-related quality of life (QoL), time off 
list (including number of temporary suspension and duration of each suspension), cost-effectiveness, 
incidence of permanent removal from list for cardiac causes; incidence of transplantation and 
cancellation of transplant due to CAD. 
Table 2: Outcome definitions 
 
Outcome  
Definition (31-32) 
Cardiovascular death 
 
Cardiovascular death is defined as any death with a cardiovascular cause 
and includes those deaths after a cardiovascular procedure (eg, 
percutaneous coronary intervention), cardiac arrest, myocardial 
infarction, pulmonary embolus, stroke, and haemorrhage or deaths due 
to an unknown cause. Non cardiovascular death is defined as any death 
owing to a clearly documented non cardiovascular cause (eg, trauma, 
infection, malignancy). 
Myocardial infarction 
Myocardial Infarction (MI) is defined as the presence of any 1 of the 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 16 of 30 
 
following 3 criteria:  
1. A typical rise of troponin or a typical fall of an elevated troponin 
detected at its peak post-surgery in a patient without a documented 
alternative explanation for an elevated troponin (e.g. pulmonary 
embolus) OR a rapid rise and fall of CK-MB. This criterion also requires 
that 1 of the following must also exist:  
a. Ischemic signs or symptoms (i.e., chest, arm, neck, or jaw discomfort; 
shortness of breath, pulmonary edema)  
b. Development of pathologic Q waves present in any two contiguous 
leads that are ≥ 30 milliseconds  
c. ECG changes indicative of ischemia (i.e. ST segment elevation [≥ 2mm 
in leads V1, V2, or V3 OR ≥ 1mm in other leads], ST segment depression 
[≥ 1mm], or symmetric inversion of T waves ≥ 1mm) in at least two 
contiguous leads  
d. Coronary artery intervention (i.e., PCI or CABG surgery)  
e. New or presumed new cardiac wall motion abnormality on 
echocardiography or new or presumed new fixed defect on radionuclide 
imaging  
2. Pathological findings of an acute or healing myocardial infarction  
3. Development of new pathological Q waves on an ECG if troponin 
levels were not obtained or were obtained at times that could have 
missed the clinical event 
Emergency 
revascularisation  
 
Emergency revascularisation within 1 month of presentation of new or 
progressive symptoms of coronary artery disease 
Hospitalisation with 
unstable angina 
 
Pain or equivalent with the presence of dynamic ECG changes, that 
requires hospitalisation. This classification require that 4 separate 
criteria be met: a) Worsening ischaemic discomfort b) Unscheduled 
hospitalization c) Objective evidence of myocardial ischaemia and d) 
Negative cardiac biomarkers 
Hospitalization 
 
Hospitalisation is defined as an admission to an inpatient unit or a visit 
to an emergency department that results in at least a 24-hr stay. 
Stroke 
A new focal neurologic deficit thought to be vascular in origin with signs 
and symptoms lasting >24 hours or leading to death 
Procedure Related Death 
 
Death caused by the immediate complication(s) of a Cardiovascular 
procedure 
Major bleeding 
 
Bleeding Academic Research Consortium (BARC) type 3 and 5.  
Type 3a: Overt bleeding plus hemoglobin drop of 3 to _5 g/dL* (provided 
hemoglobin drop is related to bleed). Any transfusion with overt bleeding 
Type 3b: Overt bleeding plus hemoglobin drop _5 g/dL* (provided hemoglobin 
drop is related to bleed). Cardiac tamponade. Bleeding requiring surgical 
intervention for control (excluding dental/nasal/skin/hemorrhoid). Bleeding 
requiring intravenous vasoactive agents. 
Type 3c: Intracranial hemorrhage (does not include microbleeds or 
hemorrhagic transformation, does include intraspinal) Subcategories confirmed 
by autopsy or imaging or lumbar puncture. Intraocular bleed compromising 
vision 
 
Type 5: fatal bleeding 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 17 of 30 
Type 5a: Probable fatal bleeding; no autopsy or imaging confirmation but 
clinically suspicious 
Type 5b: Definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation 
Definitions adapted from: 2014 ACC/AHA Key data elements and definitions for cardiovascular 
endpoint events in clinical trials,(30)Rational, design and organization of Perioperative Ischaemic 
Evaluation (POISE) trial: A randomized controlled trial of metoprolol versus placebo in patients 
undergoing noncardiac surgery,(31) and Standardised Bleeding Definitions for Cardiovascular Clinical 
Trials.(32) 
 

 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 18 of 30 
7. STUDY DESIGN 
7.1 STUDY DESIGN DIAGRAM 
 
 
 
 
 
* guidelines provided to site Investigator but frequency determined as per clinical practice at local 
site. Patients will not be screened less than every 2 years. 
 
7.2 STUDY TYPE &DESIGN & SCHEDULE 
This trial is a pragmatic multi-centre, randomized, parallel group definitive trial incorporating an 
economic evaluation and involving sites in Canada, Australia and New Zealand. Asymptomatic wait-
listed patients will be randomised to no screening versus routine screening for CAD (i.e. Exercise 
Stress test, Myocardial Perfusion Scintigraphy or Dobutamine Stress Echo) as per the current 
standard of care at each centre. 
Intervention: Patients randomized to no screening will not undergo regular non-invasive testing for 
CAD while on the wait list unless they develop symptoms. 
Control: Patients randomized to routine screening will undergo non-invasive testing for CAD every 
year or second yearly as determined by local centre practice.  
All: Patients in either group who develop symptoms of angina or an angina equivalent at any stage 
will be investigated according to the local standard of care, which may include the use of non-
invasive or invasive cardiac testing. 
7.3 TESTING PROCEDURES 
Non-invasive cardiac screening tests: The choice of non-invasive test(s) will be according to the 
existing practice of each transplant centre. Although the accuracy of inotropic stress 
echocardiography to identify occlusive CAD is somewhat better than vasodilator stress nuclear 
perfusion imaging, both abnormal Myocardial Perfusion Scintigraphy and Dobutamine Stress Echo 
have prognostic value for cardiac events and mortality in patients with renal failure, and are used 
extensively in clinical practice.(11, 33) The type of test used will be documented in all instances. 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 19 of 30 
Investigation and management of an abnormal screening test: The management of an abnormal 
screening test including performance of coronary angiography as well as treatment of coronary 
stenoses will be carried out as per the usual standard of care in individual transplant centres and will 
not be influenced by the investigators or study personnel in any way. 
7.2          STUDY TYPE & DESIGN & SCHEDULE 
This trial is a pragmatic multi-centre, randomized, parallel group definitive trial incorporating an 
economic evaluation and involving sites in Canada, Australia and New Zealand. Asymptomatic 
waitlisted patients will be randomised to no screening versus routine screening for CAD (i.e. Exercise 
Stress test, Myocardial Perfusion Scintigraphy or Dobutamine Stress Echo) as per the current 
standard of care at each centre. 
 
Intervention: Patients randomized to no screening will not undergo regular non-invasive testing for 
CAD while on the wait list. 
 
Control: Patients randomized to routine screening will undergo non-invasive testing for CAD every 
year or second yearly as determined by local centre practice. 
 
All: Patients in either group who develop symptoms of angina or an angina equivalent at any stage 
will be investigated according to the local standard of care, which may include the use of non-
invasive or invasive cardiac testing. 
 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 20 of 30 
Table 4: Study schedule  
 
 
 
7.3 TESTING PROCEDURES 
 
Non-invasive cardiac screening tests: The choice of non-invasive test(s) will be according to the 
existing practice of each transplant centre. Although the accuracy of inotropic stress 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 21 of 30 
echocardiography to identify occlusive CAD is somewhat better than vasodilator stress nuclear 
perfusion imaging, both abnormal Myocardial Perfusion Scintigraphy and Dobutamine Stress Echo 
have prognostic value for cardiac events and mortality in patients with renal failure, and are used 
extensively in clinical practice.(11, 33) The type of test used will be documented in all instances. 
 
Investigation and management of an abnormal screening test: The management of an abnormal 
screening test including performance of coronary angiography as well as treatment of coronary 
stenoses will be carried out as per the usual standard of care in individual transplant centres and will 
not be influenced by the investigators or study personnel in any way. 
7.4 STANDARD CARE AND ADDITIONAL TO STANDARD CARE PROCEDURES 
Management of patients who develop clinical symptoms of CAD: Any patient, regardless of 
randomised trial allocation, developing clinical symptoms of CAD (e.g. angina, congestive heart 
failure, or new arrhythmias) will be evaluated according to the standard of care in individual 
transplant centres and may include the use of non-invasive cardiac stress testing. Management of 
symptomatic CAD including revascularization will be according to the standard of care at the local 
transplant centre. 
Other than the use of cardiac screening tests, patient management will be as per the usual standard 
of care in participating transplant centres. In both study groups, the frequency and content of clinical 
re-evaluations will be according to the existing practice of the transplant centres participating in the 
study. Such evaluations may include cardiology consultations. Clinical evaluations by the transplant 
centre during wait-listing will be recorded in both groups. Interventions to prevent cardiovascular 
disease events may be used. Study personnel will document all surgical and medical interventions 
for CAD. The use of cardio-protective medications (aspirin, beta-blockers, medications that block 
activation of the renin angiotensin system, lipid lowering agents) will be documented every six 
months in all trial participants. However, the use of lipid lowering agents, aspirin, and beta-blockers 
remain controversial due to the lack of definitive evidence regarding efficacy in ESKD patient, and 
their use is likely to vary between centres and between physicians at the same centre.(9, 34) 
Similarly behavioural therapies such as participation in weight loss, smoking cessation or healthy 
heart programs may be used. Medical and behavioural treatments will not be specified in the trial 
but will be documented by study personnel. 
7.5 RANDOMISATION 
Allocation of participants to trial groups will be done using the same web-based randomization 
system used in our pilot trial. Patients will be stratified by centre and diabetes. The randomization 
process will consist of a computer-generated random listing of the group allocations stratified as 
above in variable permuted block sizes that will not be known to the investigators. The system will 
have backup in the form of a statistician and designated research assistant at the coordinating 
centre and only these individuals will know the randomization codes. After confirming eligibility and 
obtaining consent, the study nurse will access the trial website and provide the subject’s unique ID. 
The web site will provide the next available randomization number. 
7.6 ECONOMIC METHODOLOGY 
 
Outline of the within-trial analysis 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 22 of 30 
A cost-effectiveness and cost-utility analysis of no screening compared to usual screening will be 
conducted from an Australian and Canadian health system perspective.  
 
Outcomes for the analysis 
The analysis will report the cost per MACE avoided; the cost per life year gained; and the cost per 
quality adjusted life year (QALY) gained of no screening compared to usual screening.  
 
Analysis methods  
A cost-utility analysis will be undertaken for this non-inferiority trial.  
 
Censoring of costs and outcomes 
Censoring of cost data may occur if: the cost event eg. hospitalization continues beyond the 4 year 
follow-up time; the cost data collection for some participants does not start at randomization; or if 
participants are lost to follow-up. A comparison of the clinical characteristics of participants with 
complete versus censored cost data will be tabulated. The method for addressing censored cost data 
will be determined after investigation of the pattern of missing data (e.g. missing completely at 
random, missing at random, missing not at random) using the Lin method, the Bang &Tsiatis method 
or multiple imputation methods.(35) Censoring of outcome data may occur if patients are lost to 
follow up. Survival analysis methods such as Kaplan Meier Sample Average (KMSA) or Inverse 
Probability Weighting (IPW) will be undertaken.  
 
Statistical methods for analysis of economic data 
Skewed cost data: Cost data are likely to be right skewed as they are bounded by zero (i.e. can’t be 
negative); have no upper bound, and a small number of patients will likely incur very high costs, 
affecting the mean. The cost distribution will be plotted in a histogram and non-parametric 
bootstrapping will be used for analysis. (36) 
 
Data validation 
Identification of resource use in the trial case report forms and patient diaries will be validated 
through a cross check with treating clinicians (nephrologists and cardiologists); by comparison with 
the published literature; and for Australian participants through cross checks with the Admitted 
Patient Data Collection and Medicare data.  
 
Missing data 
It is anticipated in this trial that there may be some missing quality of life or resource use data. 
Investigation of the pattern of missing data (e.g. missing completely at random, missing at random, 
missing not at random) will determine the appropriate method for handling the missing data. For 
quality of life, a weighted mean value for the group sample may be used to ‘fill in’ the missing items. 
Depending on the amount of missing data, multiple imputation will be considered.  
 
Costs 
Costs will include all CAD related health system resource use including screening and subsequent 
treatments, doctor’s visits and in-patient hospitalisations.  
 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 23 of 30 
Individual participant resource use 
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 and Canadian participants will have their records linked to regional or provincial 
administrative data to capture units of resource use including in-patient, ambulatory care, 
medication use, and physician visits. 
 
Unit costs 
Valuation of resource use will be obtained using relevant costs (Australian-Refined Diagnosis Related 
Groups (AR-DRG); CIHI CMG+, etc).)  
 
Results 
The mean and total volume of major categories of resource use (e.g. diagnostic tests; doctor’s visits; 
revascularization procedures; and hospitalisations) will be reported for each group. The difference in 
the volume of resource use for each group and 95% confidence intervals for the difference will be 
reported.  
 
Total costs 
The total cost will be calculated by multiplying the arithmetic mean cost by the number of 
participants in each group. Mean costs with standard deviations and total costs for each group will 
be reported in Australian dollars for the most recent reference year, discounted at 5% per annum. 
The difference in total costs will be assessed using the student t test and/or analysis of variance 
(ANOVA). Total costs will also be adjusted for relevant baseline characteristics (e.g. age, sex). 
 
Benefits will include:(i) quality of life, measured annually with the KDQOL-36™ and EQ-5D-5L 
surveys; (ii) the proportion of participants who avoid MACE; (iii) life years gained and (iv) QALY 
gained at year 2 (12 months post randomisation) and year 4 (study end).  
 
Participant utilities 
The EQ-5D-5L will be administered to all trial participants at baseline and every 6 months throughout 
the trial.  
 
Cost-effectiveness and cost-utility analyses 
Using the mean discounted costs in each trial arm, and the mean discounted benefits in each arm, 
the incremental cost per life year gained and cost per QALY gained of the no screening group 
compared with regular screening group will be calculated; results will be plotted on a cost-
effectiveness plane. Bootstrapping will be used to estimate a distribution around costs and health 
outcomes, and to calculate confidence intervals around incremental cost-effectiveness ratios.(39)A 
cost-effectiveness acceptability curve (CEAC) will be plotted, providing information about the 
probability that the intervention is cost-effective given a decision maker’s willingness to pay for a 
QALY gained.(39) 
 
Sensitivity analysis 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 24 of 30 
One-way sensitivity analyses will be conducted around key variables, including the most expensive 
items of resource use, and the frequency of cardiac screening in the usual care arm: i.e. every year 
versus every 2 years. Sensitivity analysis will be undertaken using an alternative QALY weight 
obtained from the SF-6D a component of the KDQOL-36™ questionnaire using country-appropriate 
tariffs. In addition, sensitivity analyses will vary the discount rate from 0-6%. 
7.7 DATA LINKAGE 
To obtain additional data for economic evaluation, we will use data linkage to link Canadian, 
Australian, and New Zealand participant records to available national / regional / provincial data 
sets. The period of interest will be from the beginning of the recruitment period to the end of the 
study period (2016-2020). In Australia, we will apply probabilistic linkage procedures to link data 
based on patient name, date of birth, sex and postcode. We will link their records to the Admitted 
Patient Data Collections and the Emergency Department Data Collections for NSW, Victoria and the 
ACT, and Medicare Australia for outpatient visits, diagnostic tests and medicines prescribed under 
the Pharmaceutical Benefits Scheme (PBS) for all jurisdictions. In New Zealand, the benefit of a 
unique National Health Index (NHI) number will allow deterministic record linkage. We will link New 
Zealand participants to the National Minimum Dataset, National Non-Admitted Patient Collection 
and the Pharmaceutical Collection. We will capture inpatient encounters, the length of stay and 
resource utilisation (hospitalisations, procedural costs), physician consultations and emergency 
services use from these databases. In Canada, unique health care codes will be linked to provincial 
data to capture resource use of inpatient (CIHI CMG+) and ambulatory care resource use (NACRS), as 
well as physician claims. Medication use will be captured every 6 months by coordinators from 
patient interview. 
 
8. STUDY POPULATION 
8.1 RECRUITMENT PROCEDURE 
Participants will be recruited through any of the participating centres. Patients will be identified 
from site kidney transplant waiting lists, and approached when attending routine waiting list review 
appointments. Patients can also be approached immediately after they are waitlisted for the first 
time or immediately before activation on the kidney transplant wait list. Study procedure will initiate 
only once the patients are active on the list.  
8.2 INCLUSION CRITERIA 
1) adults aged 18 years of age or older; 
2) dialysis-dependent and 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 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 25 of 30 
8.3 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 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. 
 
8.4 CONSENT 
Informed written consent will be requested using the approved patient information and consent 
form as per the conduct of Good Clinical Practice. Consent will be sought from participants for 
linkage of trial records to Medicare data for identification of health system resource use. In an effort 
to enhance fidelity of the study, permission to contact a treating cardiologist, if present, will be 
sought.  
9. PARTICIPANT SAFETY AND WITHDRAWAL 
9.1 RISK MANAGEMENT AND SAFETY 
Data will be formally reviewed on a 6 monthly basis by the data safety monitoring board (DSMB) 
who will receive appropriate data reports. Any recommendations from the DSMB will be 
communicate directly to the site PI.  
9.2 HANDLING OF WITHDRAWALS 
Provision for withdrawals and drop outs has been made in determining trial size, therefore 
replacements will not be required. 
10. STATISTICAL METHODS 
10.1 
SAMPLE SIZE ESTIMATION & JUSTIFICATION 
The target total sample size is 3306 patients from 23 sites (7 from Australia, 1 from NZ, 15 from 
Canada). This number of sites will provide a target number of 1000 patients from Australia, 100 from 
New Zealand and 2206 from Canada. This equates to recruitment of ≤ 4 patients per month per 
centre. This rate is feasible given current wait-list and transplant volumes from all countries. 
10.2 
POWER CALCULATIONS 
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.(41) Unpublished data 
in Australia and Canada show lower rates of 3% and 8% respectively. The lowest MACE rate would 
be observed if all patients underwent transplantation rapidly (i.e. one year wait-listing (MACE 8%), 
followed by one year of post transplant follow up (MACE 3%)). In this hypothetical scenario, the 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 26 of 30 
average MACE rate would be 5.5%. We estimate that 50% of participants will receive a kidney 
transplant during the study - therefore the majority of patient follow up time will be accrued on the 
waiting list (when the MACE rate is high) rather than after a KTX justifying our estimated average 
MACE rate of 6%. 
 
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 to 
claim no screening is non-inferior to regular screening if the absolute difference in MACE in the no 
screening group is <1.4% higher (i.e. 7.4% versus 6.0 %) than in the regular screening group (Fig 2). 
This is lower than the 2% absolute increase in MACE Canadian transplant physicians indicated would 
be unacceptable in a survey prior to our pilot trial. 
 
Enrolment of 3306 patients requires recruitment of ≤ 4 patients per month per centre. This rate is 
feasible, and was achieved in our pilot trial. Figure 2 shows the study power for MACE rates between 
5 -13% per year. These calculations take into account the different study follow-up in Canada (5 
years) and Australasia (4 years), and allow for a 10% drop-out rate. 
 
Power calculations were performed using the Non-inferiority Logrank Tests in PASS 12 (NCSS, LLC. 
Kaysville, Utah, USA. www.ncss.com).  
 
Figure 2: Study power for MACE rates 
 
10.3 
STATISTICAL METHODS TO BE UNDERTAKEN 
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. 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 27 of 30 
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 
(42). 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.  
For all time to event outcomes, a subgroup analysis will conducted to test for a statistical interaction 
(effect modification) between treatment arm and transplantation. This will be performed by 
stratifying the survival models by transplant date and testing the HRs between the two strata.  
Time off waiting list will be analysed using a negative binomial model, with an offset for total time in 
study.  
Safety outcomes will also be analysed using both intention to treat and per-protocol approaches.  
Balance between treatment arms will be assessed by comparing means for continuous variable 
characteristics, such as age, or by comparing proportion for categorical characteristics, such as sex. If 
there is any imbalance, then an adjusted analysis for any unbalanced characteristics will be 
conducted in addition to the analyses stated above, which only account for site. 
11. DATA SECURITY & HANDLING 
11.1 
DETAILS OF WHERE RECORDS WILL BE KEPT & HOW LONG WILL THEY BE STORED 
Data will be captured using REDCap and stored on servers at the Sydney Local Heath District (SLHD) 
Royal Prince Alfred data centre. Participating sites will enter data into electronic case report forms 
(eCRF) via a secure web-based data capture software tool. REDCap allows data to be inputted at 
multiple sites with web authentication, data logging and Secure Sockets Layer encryption. Records 
will be kept for a minimum of 15 years. 
The coordinating site will generate periodic data audit for quality and accuracy and provide data 
reports required for progress reports, data safety monitoring board meetings and event adjudication 
committee meetings. 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 28 of 30 
11.2 
CONFIDENTIALITY AND SECURITY 
The coordinating site will monitor data inputted by contributing sites. Users are given individual 
usernames and passwords and are granted access to the project with certain privileges. Data 
collected from individual sites will be anonymous and de-identified. Confidential data such as patient 
details will also be de-identified during the export mechanism to allow data to be analysed.  The 
backup process is maintained by SLHD Information Management and Technology Division and are 
performed daily to a separate server. 
11.3 
ANCILLARY DATA 
Ancillary data such as test reports will be uploaded onto the eCRF and will stored electronically via 
the mechanism outlined above. 
1. APPENDIX 
List of Attachments included: 
Document Name 
Version Number 
 
Date (e.g., 18 
January 2012) 
 
QOL-Health Questionnaire - EQ-5D-5L 
1.0 
June, 2015 
Kidney Disease and Quality of Life – KDQOL-36 
1.0 
2000 
 
2. REFERENCES 
 
1. Laupacis A, Keown P, Pus N, et al. A study of the quality of life and cost-utility of renal 
transplantation. Kidney Int. 1996;50(1):235 
2. Tonelli M, Wiebe N, Knoll G, et al. Systematic review: kidney transplantation compared with 
dialysis in clinically relevant outcomes. Am J Transplant. 2011;11(10):2093  
3. Australia and New Zealand Dialysis and Transplant Registry. Prevalence of End Stage Kidney 
Disease [Internet]. 2016 p. 3. Available from: 
http://www.anzdata.org.au/anzdata/AnzdataReport/38thReport/c02_anzdata_prevalence_v1.0_20
160106_web.pdf 
4. Canadian institute for health information (CIHI). Treatment of end-stage organ failure in Canada, 
Canadian organ replacement register 2005-2014 [Internet]. 2016. Available from: 
https://secure.cihi.ca/free_products/2016_CORR_Snapshot_EN(web).pdf 
5. Clayton P, Campbell S, Chadban S, et al. Chapter 8 Transplantation. Adelaide, South Australia: 
Australia and New Zealand Dialysis and Transplant Registry 2012. 

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 29 of 30 
6. McDonald SP, Clayton P, Grace B, et al. Chapter 7 Transplant Waiting list. Adelaide, South 
Australia: Australia and New Zealand Dialysis and Transplant Registry 2012. 
7. Meier-Kriesche HU, Port FK, Ojo AO, et al. Effect of waiting time on renal transplant outcome. 
Kidney Int. 2000;58(3):1311 
8. Wolfe R, Ashby V, Milford E, et al. Comparison of mortality in all patients on dialysis, patients on 
dialysis awaiting transplantation, and recipients of a first cadaveric transplant. NEJM. 1999;341:1725 
9. Pilmore H, Dent H, Chang S, et al. Reduction in cardiovascular death after kidney transplantation. 
Transplantation. 2010;89(7):851 
10. Lentine KL, Brennan DC, Schnitzler MA. Incidence and predictors of myocardial infarction after 
kidney transplantation. J Am SocNephrol. 2005;16(2):496 
11. Lentine KL, Costa SP, Weir MR, et al. Cardiac disease evaluation and management among kidney 
and liver transplantation candidates: a scientific statement from the american heart association and 
the american college of cardiology foundation. J Am CollCardiol. 2012;60(5):434  
12. USRDS. Annual Data Report: Atlas of End Stage Renal Disease in the United States. National 
Institute of Health, National Institute of Diabetes and Digestive and Kidney Disease, 2012.  
13. Herzog CA, Littrell K, Arko C, et al. Clinical characteristics of dialysis patients with acute 
myocardial infarction in the United States: a collaborative project of the United States Renal Data 
System and the National Registry of Myocardial Infarction. Circulation. 2007;116(13):1465 
14. U.S. Department of Health and Human Services HRaSA, Healthcare Systems Bureau, Division of 
Transplantation. 2009 Annual Report of the U.S. Organ Procurement and Transplantation Network 
and the Scientific Registry of Transplant Recipients: Transplant Data 1999-2008. Rockville, MD: 2009. 
15. ANZOD. Chapter 4 Donor Profile, ANZOD Annual Report Adelaide, South Australia: Australia and 
New Zealand Organ Donation Registry, 2013. 
16. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis. 
2005 Apr;45(4 Suppl 3):S1 
17. Manske CL, Wang Y, Rector T, et al. Coronary revascularisation in insulin-dependent diabetic 
patients with chronic renal failure. Lancet. 1992 Oct 24;340(8826):998 
18. Gill JS, Ma I, Landsberg D, et al. Cardiovascular events and investigation in patients who are 
awaiting cadaveric kidney transplantation. J Am SocNephrol. 2005;16(3):808 
19. Landray MJ, Thambyrajah J, McGlynn FJ, et al. Epidemiological evaluation of known and 
suspected cardiovascular risk factors in chronic renal impairment. Am J Kidney Dis. 2001 
Sep;38(3):537 
20. Fuster V, Moreno PR, Fayad ZA, et al. Atherothrombosis and high-risk plaque: part I: evolving 
concepts. J Am CollCardiol. 2005 Sep 20;46(6):937 
21. Corti R, Fuster V, Badimon JJ. Pathogenetic concepts of acute coronary syndromes. J Am 
CollCardiol. 2003 Feb 19;41(4 Suppl S):7S 
22. Tuman KJ, McCarthy RJ, March RJ, et al. Effects of epidural anesthesia and analgesia on 
coagulation and outcome after major vascular surgery. AnesthAnalg. 1991 Dec;73(6):696 
23. Ellis SG, Hertzer NR, Young JR, et al. Angiographic correlates of cardiac death and myocardial 
infarction complicating major nonthoracic vascular surgery. Am J Cardiol. 1996 May 15;77(12):1126 
24. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on Perioperative 
Cardiovascular Evaluation and Care for Noncardiac Surgery. J Am CollCardiol. 2007 Oct;50(17):1707  
25. Jeantet A, Piccoli GB, Malfi B, et al. Preparation of candidates for renal transplantation: cost 
analysis. Transplant Proc. 2004 Apr;36(3):455  

 
 
 
 
 
 
 
 
 
Study Name: CARSK 
 
CONFIDENTIAL 
 
Protocol Number: 1 
Version & date: version 5, dated 28 August 2018 
Page 30 of 30 
26. Friedman SE, Palac RT, Zlotnick DM, et al. A call to action: variability in guidelines for cardiac 
evaluation before renal transplantation. Clin J Am SocNephrol. 2011 May;6(5):1185  
27. Schedule MB. Medicare Benefits Schedule - Item 61307: Department of Health, Australian 
Government; 2014 [cited 2014 1 March]. Available from: 
http://www9.health.gov.au/mbs/search.cfm.  
28. Kasiske BL, Malik MA, Herzog CA. Risk-stratified screening for ischemic heart disease in kidney 
transplant candidates. Transplantation. 2005;80(6):815  
29. Patel AD, Abo-Auda WS, Davis JM, et al. Prognostic value of myocardial perfusion imaging in 
predicting outcome after renal transplantation. Am J Cardiol. 2003 Jul 15;92(2):146  
30. Hicks K, Tcheng J, Bozkurt B, Chaitman B, Cutlip D, Farb A et al. 2014 ACC/AHA Key Data Elements 
and Definitions for Cardiovascular Endpoint Events in Clinical Trials. Journal of the American College 
of Cardiology. 2015;66(4):403-469. 
31. Rationale, design, and organization of the PeriOperativeISchemic Evaluation (POISE) Trial: A 
randomized controlled trial of metoprolol versus placebo in patients undergoing noncardiac surgery. 
American Heart Journal. 2006;152(2):223-230. 
32. Mehran R, Rao S, Bhatt D, Gibson C, Caixeta A, Eikelboom J et al. Standardized Bleeding 
Definitions for Cardiovascular Clinical Trials: A Consensus Report From the Bleeding Academic 
Research Consortium. Circulation. 2011;123(23):27 
33.  Wang L, Fahim M, HAyen A, et al. Cardiac testing for coronary artery disease in potential kidney 
transplant recipients: a systematic review of test accuracy studies. Am J Kidney Dis. 2011;57(3):476  
34 Palmer SC, Di Marco L, Razavian M, et al. Antiplatelet agents for chronic kidney disease. Cochrane 
Database Syst Rev. 2013;2:CD008834.pub2  
35. Glick HA; Doshi JA, Sonnad SS, Polsky D. 2014. Economic evaluation in clinical trials. 2nd edition. 
pp128-133. Oxford University Press. Oxford, UK. 
36. Briggs AH, Gray AM. (1998) The distribution of healthcare costs and their statistical analysis for 
economic evaluation. Journal of Health Services Research and Policy. 3. pp233-45. 
37. Glick HA; Doshi JA, Sonnad SS, Polsky D. 2014. Economic evaluation in clinical trials. 2nd edition. 
pp82-85. Oxford University Press. Oxford, UK. 
38. Marra CA, Woolcott JC, Kopec JA, SHonjania K, Offer R, Brazier JE, Esdaile JM, Anis AH. A 
comparison of generic, indirect utility measures (the HUI2, HUI3, SF-6D, and the EQ-5D) and disease-
specific instruments (the RAQoL and the HAQ) in rheumatoid arthritis. SocSci 
Med. 2005 Apr;60(7):1571-82. 
39. Fenwick E1, O'Brien BJ, Briggs A. Cost-effectiveness acceptability curves--facts, fallacies and 
frequently asked questions. Health Econ. 2004 May;13(5):405-15 
40. Kasiske BL, Israni AK, Snyder JJ, et al. Design considerations and feasibility for a clinical trial to 
examine coronary screening before kidney transplantation (COST). Am J Kidney Dis. 2011 
Jun;57(6):908  
41. Fishbane S. Cardiovascular risk evaluation before kidney transplantation. J Am SocNephrol. 
2005 Apr;16(4):843-5. 
42. Andersen P, Gill R. Cox's Regression Model for Counting Processes: A Large Sample Study. Ann 
Statist. 1982;10(4):1100-1120.