Multicomponent Intervention to Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) in Patients With Chronic Kidney Disease: A Pragmatic, Registry-based, Cluster-Randomized Clinical Trial
Phase: NA
Conditions: Kidney Diseases, Kidney Failure, End Stage Renal Disease
Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

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Title: Multicomponent Intervention to Enhance Access to Kidney Transplantation and Living 
Kidney Donation (EnAKT LKD) in Patients with Chronic Kidney Disease: A Pragmatic, Registry-
based, Cluster-Randomized Clinical Trial 
 
Protocol Trial Registration: NCT03329521 
 
Date: August 10th, 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Compilation 
 
All documents are from the EnAKT LKD study. 
The original protocol was approved by the research ethics board prior to randomization which occurred 
in February 2017 and prior to the Chronic Kidney Disease programs being notified of their assigned 
allocation in February 2017. 
 
The final protocol was submitted for publication on December 20, 2020, and accepted for 
publication on January 2, 2021.  
 
Summary of changes for the protocol were originally posted online on May 4, 2021, at ClinicalTrials.gov 
NCT03329521. It documents changes made after the original protocol version on August 30, 2017, and 
the protocol published in the Canadian Journal of Kidney Health and Disease on January 2, 2021. 
 
The original and only version of the statistical analysis plan was submitted for publication on 
June 23, 2022, and accepted for publication on September 5, 2022.  
 
The original and only protocol for the process evaluation was approved by the research 
ethics board on October 15, 2020. The original and only version of the protocol for the process 
evaluation was submitted for publication on August 16, 2021 and accepted for publication on January 
25, 2022.   
 
 
 
 

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Table of Contents 
 
1. Original protocol………………………………………………………………………………………………………page 4 
2. Final protocol……………………………………………………………………………………………………………page 10 
3. Table of protocol updates………………………………………………………………………………………..page 11 
4. Final statistical analysis plan…………………………………………………………………………………….page 32 
5. Final process evaluation protocol…………………………………………………………………………….page 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Western University Health Sciences Research Ethics Board (approval #108408) Version date: 30/08/2017 
 
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A multicomponent quality improvement program to improve access to kidney 
transplantation and living kidney donation  
Principal Investigator 
Dr. Amit Garg MD, PhD 
Schulich School of Medicine and Dentistry/Epidemiology & Biostatistics  
London Health Sciences Centre 
amit.garg@lhsc.on.ca  
 
Lay summary of the study 
Despite the advantages of kidney transplantation over dialysis (i.e., improved survival) only 
42.5% of Canadians with end-stage renal disease have received a kidney transplant. The best 
way to improve access to kidney transplantation is unknown. A multicomponent kidney 
transplant quality improvement program was developed in collaboration with the Ontario 
Renal Network and Trillium Gift of Life Network to improve access to kidney transplantation in 
Ontario, Canada. The multicomponent program includes four main components: data (e.g., 
reports to renal programs about their program’s performance), education (e.g., education 
toolkits), peer mentorship (e.g., kidney transplant recipients can mentor kidney disease 
patients), and administration (e.g., helping finance nursing staff time for transplant education). 
The goal of this multicomponent program is to increase kidney transplant referrals and kidney 
transplant rates in Ontario renal programs which care for individuals with kidney disease. 
 
Study rationale  
Compared to dialysis, kidney transplantation is associated with improved survival and quality of 
life with kidney transplantation saving an average of 4.4 life years per patient (1-3). Moreover, 
kidney transplantation has significantly lower healthcare system costs saving approximately 
$250,000 (CAD) per patient over a five-year period (4). However, despite these advantages, 
only 42.5% of the 41,931 Canadians with end-stage renal disease (ESRD) have received a kidney 
transplant (5). There are multiple reasons why ESRD patients who may benefit from a kidney 
transplant do not receive one with potential barriers to kidney transplantation existing at the 
level of the patient (e.g., patient does not have a good understanding of transplantation to 
make an informed decision about treatment options), potential living kidney donor (e.g., 
financial concern), healthcare provider (e.g., insufficient knowledge on transplantation), renal 
program (e.g., inefficient processes), and at the level of the transplant centre (e.g., lack of 
standard criteria for transplant acceptance). Moreover, many ESRD patients would like to 
receive a transplant but there are too few deceased donor organs available to meet demand 
(6). Although, patients can receive a kidney from a living donor there are also multiple barriers 
to living donation (e.g., difficulty finding a donor) (7). Recognizing the need to address barriers 
to kidney transplantation one of the Ontario Renal Network's (ORN) mandates is to improve 
access to kidney transplantation. To accomplish this, in collaboration with the Trillium Gift of 
Life Network (TGLN), the ORN plans to launch a multicomponent kidney transplant quality 
improvement program across the 26 renal programs in Ontario. Using a community-based 
participatory research approach and the best available evidence the multicomponent program 
was developed. The program will be comprised of four main components: 1. Data (e.g., provide 

Western University Health Sciences Research Ethics Board (approval #108408) Version date: 30/08/2017 
 
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reports to renal programs about their performance using best practices in audit and feedback) 
(8); 2. Education (e.g., education toolkits for renal program providers, renal patients and 
families, and potential donors) (9-12); 3. Peer mentorship (e.g., kidney transplant recipients and 
living kidney donors can mentor individuals who are going through the transplant process to 
provide support) (13-15); and 4. Administration (e.g., helping finance nursing staff time for 
transplant education within each renal program). To our knowledge, this will be the first 
province in Canada to implement and evaluate a multicomponent kidney transplant quality 
improvement program to improve access to kidney transplantation with the goal of increasing 
the number of kidney transplant referrals and the number of kidney transplants. 
 
Purpose and objectives  
Purpose: Many pre-dialysis and dialysis patients would likely benefit from a kidney transplant, 
yet do not receive one. Recognizing this, one of the goals of the Ontario Renal Network (ORN), 
in collaboration with the Trillium Gift of Life Network (TGLN), is to improve access to kidney 
transplantation through implementing and evaluating a multicomponent kidney transplant 
quality improvement program across Ontario's regional renal programs and their associated 
multidisciplinary kidney care clinics.  
Objectives: The primary objective is to determine if a multicomponent kidney transplant quality 
improvement program increases the kidney transplant referral rate in Ontario renal programs. 
Specifically, we will be comparing renal program level kidney transplant referral rates between 
the multicomponent quality improvement group and the standard-of-care group. We will also 
be examining several secondary outcomes, including: 1) proportion of potential living kidney 
donors contacting a transplant centre; 2) rate of kidney transplant evaluation; 3) rate of kidney 
transplant wait listing; 4) proportion of patients approved to receive a living kidney donor 
transplant; 5) rate of kidney transplantation (living and deceased donor kidney transplants 
examined separately); and 6) rate of pre-emptive kidney transplantation (i.e., no dialysis prior 
to transplantation). All secondary outcomes will also be examined at the level of the renal 
program. 
 
Study design and methodology 
To support a more defensible evaluation of the multicomponent kidney transplant quality 
improvement program a parallel two-arm cluster randomized control trial design will be used 
where the 26 Ontario regional renal programs (the clusters) will be randomized using covariate-
constrained randomization in a 1:1 ratio to receive a multicomponent quality improvement 
program or the standard of care that is currently provided by the ORN. After the trial is over the 
other half of the renal programs will receive the multicomponent improvement program. 
Administrative databases at ICES will be utilized to conduct the randomization with renal 
programs, which care for pre-dialysis and dialysis patients, being randomized on a single date. 
Each of the 26 renal programs in Ontario will be a 'cluster'. Thirteen of the 26 renal programs in 
Ontario will be randomized to receive the multicomponent kidney transplant quality 
improvement program in September 2017 (early), while the other 13 programs will receive the 
standard of care. In Fall 2019 the standard of care group will begin receiving the 
multicomponent program. The multicomponent program will have four main components: 1. 

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Data (e.g., provide reports to renal programs about their performance using best practices in 
audit and feedback); 2. Education (e.g., education toolkits for renal program providers, renal 
patients and families, and potential donors); 3. Peer mentorship (e.g., kidney transplant 
recipients and living kidney donors can mentor individuals who are going through the 
transplant process to provide support); and 4. Administration (e.g., helping finance nursing staff 
time for transplant education within each renal program). The primary outcome of interest is 
referral for transplantation, defined as the date the transplant centre receives a referral from 
the renal program. All baseline and outcome data will be retrieved from routinely collected 
administrative healthcare data housed at ICES. 
Inclusion criteria for participant recruitment. 
All of Ontario's 26 regional renal programs and their associated multidisciplinary kidney care 
clinics (MCKC) will be included. These programs provide care for all chronic dialysis patients. 
Each CKD program also provides a MCKC for pre-dialysis patients. We will be restricting to pre-
dialysis patients with an eGFR <15mL/min/1.73m2 (defined as two outpatient eGFR 
measurements meeting this criterion within the last year) OR a 2-year KFRE ≥25% (defined as 
two KFRE measurements meeting this criterion within the last year).   
 
Considering your inclusion criteria listed above, what is the basis to exclude a potential 
participant? 
Not applicable, we will be including all Ontario renal programs. 
 
If using patients, describe the usual standard of care at the study site(s) for this population  
Currently, there is no standard of care to improve access to kidney transplantation at the 
Ontario renal programs. Renal programs may provide education to their patients on treatment 
modalities (i.e., hemodialysis, peritoneal dialysis, transplant). The renal programs also currently 
provide program-level performance reports on different metrics (e.g., transplant rates); 
however, these are not based on best practices in audit and feedback. 
 
Describe the study procedures and any study specific testing that will be done, outside of 
standard care. 
The multicomponent kidney transplant quality improvement program will be at the level of the 
renal program, rather than the individual patient. As a result, all patients within a program will 
receive similar care. 
 
How many participants over the age of 18 will be included at all study locations?  
26 renal programs and their associated multidisciplinary kidney care clinics.  
 
How many participants under the age of 18 will be included at all study locations?  
No renal programs treat children exclusively; however, there could be some children 
transitioning to adult care.  
 
 
 

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Describe the method(s) of data analysis. 
All baseline and outcome data will be ascertained from healthcare data housed at ICES. Under 
section 45 of Ontario's Personal Health Information Privacy Act ICES is considered a prescribed 
entity. Therefore, health information custodians, such as, physicians, long-term care homes, or 
hospitals, can disclose personal health information without consent to ICES about their 
patients. As a result, this evaluation can be performed without requiring the direct collection of 
patient identifiers or information. The statistical analyses will be conducted using an intention 
to treat analysis. To determine if a statistically significant difference in referral rates (primary 
outcome) exists between the multicomponent kidney transplant quality improvement program 
and the standard of care group a Poisson regression model will be used which includes 
potential confounders but not the intervention status. This method has been found in 
simulation studies to be robust even when there are a small number of clusters and when the 
distribution of cluster sizes is skewed. Using ICES administrative databases the renal programs' 
patients (dialysis and pre-dialysis) will be followed for approximately two-years censoring at 
death. All analyses will be conducted using the Statistical Analysis Software (SAS) version 9.4 
and all analytics will be conducted at ICES Western by an ICES analyst. 
 
How will the results of this study be made public? 
Peer reviewed publication|Presentation|Other 
 
If report to participants or other is selected above, please explain 
Other can be described as providing a summary report of our findings which would include 
detailed statistical methodology to the Ontario Renal Network (ORN); due to word limit 
restrictions often imposed in peer reviewed publications we like to provide more detailed 
methods and resources to aid with the interpretation of results for non-researchers.  
 
Briefly provide any plans for provision of feedback of results to the participants. 
The results will be presented to patient representatives who will assist with interpreting, 
drafting, and developing a dissemination plan to communicate the results. Communications 
teams from the ORN and TGLN will be used to distribute results and publish information and 
resources. Results will be published in an open-access manuscript. Study findings will be 
disseminated through social media and news media releases. 
Does this study include any use of deliberate deception or withholding of key information 
that may influence a participant's performance or response? 
No 
 
List any potential anticipated benefit to the participants. 
The renal programs may be able to help their patients make more informed decisions around 
kidney transplantation by providing them with enhanced educational resources and through 
peer mentorship. All four parts of the multicomponent program, including data and 
administration, will aim to improve access to kidney transplantation at renal programs, which 
would benefit their patients given kidney transplantation has been found to be associated with 
improved survival and quality of life compared to dialysis. 

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List the potential benefits to society. 
We hypothesize that the multicomponent kidney transplant quality improvement program will 
increase kidney transplant referral rates in Ontario's renal programs, thereby increasing access 
to kidney transplantation and increasing the number of kidney transplants in Ontario. 
Increasing the number of kidney transplants could result in significant financial savings to the 
Ontario healthcare system; kidney transplantation has significantly lower healthcare system 
costs compared to dialysis saving approximately $250,000 (CAD) per patient over a five-year 
period. These healthcare system savings could benefit all Ontario residents allowing these 
healthcare financial savings to be redistributed to other areas. 
 
List any potential risks to study participants. 
 We are simply evaluating a program that the ORN is already planning on rolling out to their 
renal programs. Thus, we believe that participating in this multicomponent kidney transplant 
quality improvement program poses no more than a minimal risk to patients. 
 
List any potential inconveniences to daily activities. 
It is not anticipated that the multicomponent kidney transplant quality improvement program 
will impact renal programs' and their patients' daily activities. For example, renal programs will 
provide education initiatives to their patients when they were already scheduled to attend the 
renal program. Moreover, regarding renal program staff, part of the multicomponent program 
involves funding dedicated staff time to implement this strategy. 
Since our unit of randomization and unit of analysis are renal programs, participants will not be 
approached to be recruited for this study.  
Is this an industry sponsored protocol? 
No 
 
 
 

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References 
1. 
Canadian Institute for Health Information. Canadian Organ Replacement Register 
Annual Report: Treatment of End-Stage Organ Failure in Canada, 2000 to 2009. 
Ottawa, ON: CIHI; 2011. 
2. 
Rana A, Gruessner A, Agopian VG, et al. Survival benefit of solid-organ transplant in 
the United States. JAMA surgery. 2015;150:252-9.  
3. 
Ortiz F, Aronen P, Koskinen PK, et al. Health-related quality of life after kidney 
transplantation: who benefits the most? Transpl Int. 2014;27:1143-51.  
4. 
Kidney Foundation of Canada. Facing the Facts. 2012. 
http://www.kidney.ca/document.doc?id=1376. Accessed July 7, 2015. 
5. 
Canadian Institute for Health Information. Canadian Organ Replacement Register 
Annual Report: Treatment of End-Stage Organ Failure in Canada, 2003 to 2012. 
Ottawa, ON: CIHI; 2014. 
6. 
Canadian Institute for Health Information. Canadian Organ Replacement Register 
Annual Report: Treatment of End-Stage Organ Failure in Canada, 2002 to 2011. 
Ottawa, ON: CIHI; 2013. 
7. 
Barnieh L, McLaughlin K, Manns BJ, Klarenbach S, Yilmaz S, Hemmelgarn BR. Barriers 
to living kidney donation identified by eligible candidates with end-stage renal 
disease. Nephrol Dial Transplant. 2011;26:732-8.  
8. 
Brehaut JC, Colquhoun HL, Eva KW, et al. Practice Feedback Interventions: 15 
Suggestions for Optimizing Effectiveness. Ann Intern Med. 2016;164:435-41. 
9. 
Waterman AD, Peipert JD, Goalby CJ, Dinkel KM, Xiao H, Lentine KL. Assessing 
Transplant Education Practices in Dialysis Centers: Comparing Educator Reported 
and Medicare Data. Clin J Am Soc Nephrol 2015; 10:1617-2.  
10. 
LaPointe Rudow D, Hays R, Baliga P, et al. Consensus conference on best practices in 
live kidney donation: recommendations to optimize education, access, and care. Am 
J Transplant. 2015;15(4):914-22.  
11. 
Skelton SL, Waterman AD, Davis LA, Peipert JD, Fish AF. Applying best practices to 
designing patient education for patients with end-stage renal disease pursuing 
kidney transplant. Prog Transplant. 2015;25:77-84.  
12. 
Waterman A HS, Stanley SL, Barrett AC, Millinger R. Improving education increases 
dialysis patients' pursuit of transplant: Explore Transplant RCT findings. In: American 
Transplant Congress: May 30-June 3 2009; Boston, MA: American journal of 
transplantation; 2009: 360. 
13. 
Hughes J, Wood E, Smith G. Exploring kidney patients' experiences of receiving 
individual peer support. Health expectations 2009;12:396-406.  
14. 
Marlow NM, Kazley AS, Chavin KD, Simpson KN, Balliet W, Baliga PK. A patient 
navigator and education program for increasing potential living donors: a 
comparative observational study. Clin Transplant. 2016;30:619-27.  
15. 
Sullivan C, Leon JB, Sayre SS, et al. Impact of navigators on completion of steps in the 
kidney transplant process: a randomized, controlled trial. Clin J Am Soc Nephrol. 
2012;7:1639-45.  
 

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Final protocol 
Reference:  
Yohanna S, Naylor KL, Mucsi I, McKenzie S, Belenko D, Blake PG, Coghlan C, Dixon SN, Elliott L, Getchell 
L, Ki V, Nesrallah G, Patzer RE, Presseau J, Reich M, Sontrop JM, Treleaven D, Waterman AD, Zaltzman J, 
Garg AX. A Quality Improvement Intervention to Enhance Access to Kidney Transplantation and Living 
Kidney Donation (EnAKT LKD) in Patients With Chronic Kidney Disease: Clinical Research Protocol of a 
Cluster-Randomized Clinical Trial. Can J Kidney Health Dis. 2021 Apr 15;8:2054358121997266. doi: 
10.1177/2054358121997266. eCollection 2021. 

EnAKT LKD 
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Table of Protocol Updates 
** Protocol updates were made without reviewing any between-group trial outcome data (viewing and analysis only occurred after the trial period was 
over and the final version of the statistical analysis plan was accepted for publication) and were done after the start of the EnAKT LKD Trial period 
(November 1, 2017). ** 
 
Revision 
Date of Revision  
Details of Revision 
Rationale 
Official Title 
August 10, 2020 
 
 
 
 
 
 
 
 
 
August 10, 2023 
Changed from: A Protocol to Evaluate the Effectiveness of a Multi-
component Initiative to Enhance Access to Kidney Transplantation and 
Living Donation: the Enhance Access to Kidney Transplantation and Living 
Kidney Donation Trial 
Changed to: Quality Improvement Intervention to Enhance Access to 
Kidney Transplantation and Living Kidney Donation (EnAKT LKD) in 
Patients with Chronic Kidney Disease: A Pragmatic, Registry-based, 
Cluster-Randomized Clinical Trial  
 
Added clarification: Novel Multicomponent Intervention to Improve 
Patient Access to Kidney Transplantation and Living Kidney Donation: the 
EnAKT LKD Cluster-Randomized Clinical Trial 
We changed the title to provide more details on the 
trial design. The change was also made to align the 
title with the published trial protocol.   
 
 
 
 
 
 
At the manuscript review stage, reviewers suggested 
that the trial be described as a “multicomponent 
intervention” as this more accurately described the 
trial. Therefore, it is no longer described as a “quality 
improvement intervention”.  No changes were made 
to the trial, rather this was just a wording change. 
Throughout this document, it should now be referred 
to as a “multicomponent intervention” to align with 
the final published manuscript results. For brevity 
sake, we are only making this change here in this table 
of protocol updates.  
Study 
Description (Brief 
Summary) 
August 10, 2020 
 
 
 
 
 
 
 
 
 
 
Changed from: Compared to dialysis, kidney transplantation is associated 
with improved survival, better quality of life and substantial cost savings 
to healthcare systems. Despite these advantages, many individuals with 
kidney failure never receive a kidney transplant. A multi-component 
quality improvement initiative was developed to enhance access to 
kidney transplantation and living kidney donation in Ontario's chronic 
kidney disease (CKD) programs. These CKD programs provide care to 
individuals with reduced kidney function. The initiative includes four main 
components: 1. Data (e.g., data collection and reports to CKD programs 
about their transplant related performance); 2. Education (e.g., education 
toolkits for CKD program staff, kidney patients and families, including 
The four main trial components and their delivery 
have not changed; we have simply refined how we 
describe these components. Please refer to our 
published trial protocol for further details on each of 
the intervention components. 
 
 
 
 
 
 

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Revision 
Date of Revision  
Details of Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
June 23, 2022 
living kidney donor candidates); 3. Transplant Ambassadors (e.g., kidney 
transplant recipients and living kidney donors who discuss transplantation 
and living donation to patients and their families) and 4. Administration 
(e.g., provincial administrative support and resources provided to CKD 
programs to support local work). This trial will provide high-quality 
evidence about the effectiveness of a multi-component quality 
improvement initiative aimed to enhance access to kidney 
transplantation and living kidney donation. 
Changed to: Compared to dialysis, kidney transplantation is associated 
with improved survival, better quality of life and substantial cost savings 
to healthcare systems. Despite these advantages, many individuals with 
kidney failure will never receive a kidney transplant. A multi-component 
quality improvement intervention (vs. usual care) provided in chronic 
kidney disease (CKD) programs located in Ontario, Canada was developed 
to determine if it can enable more patients with no recorded 
contraindications to kidney transplant to complete more steps towards 
receiving a kidney transplant. These CKD programs provide care to 
individuals with CKD (including patients approaching the need for dialysis 
and patients receiving dialysis). The intervention has four main 
components: (1) local quality improvement teams and administrative 
support; (2) tailored education and resources for staff, patients, and living 
kidney donor candidates; (3) support from kidney transplant recipients 
and living kidney donors (i.e. Transplant Ambassador Program); and (4) 
program-level performance reports and oversight by program leaders. 
The Enhance Access to Kidney Transplantation and Living Kidney Donation 
(EnAKT LKD) trial will provide high-quality evidence on whether a multi-
component quality improvement intervention helps patients complete 
more steps towards receiving a kidney transplant. 
Added Clarification (Only the wording of the first component changed and 
the wording of all other components stayed the same): (1) support for 
local quality improvement teams and administrative needs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The four main trial components and their delivery 
have not changed; we have simply refined how we 
describe the first component. Please refer to our 
published statistical analysis plan. 
Study 
Description 
(Detailed 
Description) 
August 10, 2020 
 
 
 
Added:   
1.  Statement of the health problem or issue: 
Compared with dialysis, a kidney transplant offers patients a 
better quality of life and many gain 10 or more years of life 
We have provided more details on the trial for people 
to view on ClinicalTrials.gov as per our published trial 
protocol. 
 

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Revision 
Date of Revision  
Details of Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
expectancy. A transplant also costs the healthcare system less—
over a five-year period. Living donor transplants offer further 
advantages, including superior graft and patient survival 
compared with deceased donor transplants. Unfortunately, 
many patients with kidney failure who would benefit from a 
transplant will never receive one. There is a chronic shortage of 
organs from deceased donors, and in Canada, the rate of living 
donor kidney transplantation has stagnated. In addition to the 
shortage of transplantable kidneys, several other barriers 
impede patient access to transplantation.  
2. Objective of your project: To determine if a quality improvement 
intervention provided in chronic kidney disease (CKD) programs 
(vs. usual care) enables more patients with no recorded 
contraindications to kidney transplant to complete more steps 
towards receiving a kidney transplant. 
3. How will you undertake your work?  We will conduct a pragmatic 
two-arm, parallel-group, open-label, registry-based, cluster-
randomized clinical trial—the Enhance Access to Kidney 
Transplantation and Living Kidney Donation (EnAKT LKD) trial. 
Our study will include the 26 chronic kidney disease (CKD) 
programs in Ontario, Canada which are expected to care for over 
10,000 adult patients with CKD (including patients approaching 
the need for dialysis and patients receiving dialysis) with no 
recorded contraindications to a kidney transplant during the 
trial. Patients in 13 of the 26 CKD programs will receive a quality 
improvement intervention or usual care. The intervention has 
four main components: (1) local quality improvement teams and 
administrative support; (2) tailored education and resources for 
staff, patients, and living kidney donor candidates; (3) support 
from kidney transplant recipients and living kidney donors; and 
(4) program-level performance reports and oversight by program 
leaders.  Patients in the other 13 programs will receive usual care 
and will continue to support access to kidney transplantation and 
living kidney donation as usual.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Revision 
Date of Revision  
Details of Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
June 23, 2022 
 
4. What is unique/innovative about your project?  An investigator 
usually needs to study a large number of patients in a clinical trial 
to reliably understand the effects of a treatment. Normally, a 
study with 10,000 patients would cost more than $10 million 
dollars to conduct; however, this study will provide a reliable 
answer to the question being asked and can be done at a fraction 
of the cost. This is because we will use data already collected by 
the healthcare system. The investigator will be able to analyze 
these healthcare data at the end of the study. This means that 
the study will cost less than a traditional clinical trial. This 
pragmatic trial includes all CKD programs in the province of 
Ontario. By including patients from a variety of backgrounds, the 
results of the trial should be broadly generalizable. 
5. What is the impact of the proposed research? The EnAKT LKD 
trial will provide high-quality evidence on whether a multi-
component quality improvement intervention helps patients 
complete more steps towards receiving a kidney transplant.   
This is important as compared to dialysis, kidney transplant 
offers patients a better quality of life and many gain 10 or more 
years of life expectancy. A transplant also costs the healthcare 
system less. If our intervention is successful, more transplants 
may ultimately be performed and result in improved survival and 
a better quality of life for patients with CKD. Kidney 
transplantation achieves the triple aim in healthcare: better 
outcomes, better experience of care, and lower costs.  
Added Clarification:  
How will you undertake your work?  (Only bolded part added): We will 
conduct a pragmatic, 2-arm, parallel-group, open-label, registry-based, 
cluster-randomized, superiority, clinical trial —the Enhance Access to 
Kidney Transplantation and Living Kidney Donation (EnAKT LKD) trial. 
How will you undertake your work? (Only the wording of the first 
component changed and the wording of all other components stayed the 
same): The intervention has four main components: (1) support for local 
quality improvement teams and administrative needs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No change was made to the design of the trial, rather 
we added the term superiority, to align with the 
wording in our published statistical analysis plan. This 
trial was always a superiority trial. 
No change was made to the trial intervention, rather 
we updated the wording of the first component of the 
intervention to align with our published statistical 
analysis plan. 

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Revision 
Date of Revision  
Details of Revision 
Rationale 
How will you undertake your work?  (Only bolded part added): Patients in 
the other 13 programs will receive usual care and will continue to receive 
support in accessing kidney transplantation and living kidney donation as 
usual. 
What is unique /innovative about your project? (Only bolded sections 
changed):  An investigator usually needs to study a large number of 
patients in a clinical trial to reliably understand the effects of an 
intervention.  Normally, a study with 10,000 patients would cost more 
than $10 million dollars to conduct; however, this study will provide a 
reliable answer to the question being asked and can be done at a fraction 
of the cost. This is because we will use data routinely collected by the 
healthcare system. The investigator will be able to analyze these 
healthcare data at the end of the study. This means that the study will 
cost less than a traditional clinical trial. Also unique to this trial, is that 
the intervention was embedded and delivered in routine care. 
No change to the trial delivery was made we just 
adjusted the wording to provide more clarity. 
 
 
No changes to the trial were made we were simply 
updating the terminology to align with our published 
statistical analysis plan. We also included an additional 
unique feature of our project that we thought should 
be emphasized; again, no change was made to the 
trial delivery. 
 
Objective 
August 10, 2020 
Changed from: To determine if a multi-component kidney transplant 
quality improvement program increases the kidney transplant referral 
rate in Ontario renal programs. Specifically, we will be comparing renal 
program level kidney transplant referral rates between the multi-
component quality improvement group and the standard-of-care group.  
Changed to: To determine if a quality improvement intervention provided 
in chronic kidney disease (CKD) programs (vs. usual care) enables more 
patients with no recorded contraindications to kidney transplant to 
complete more steps towards receiving a kidney transplant.  
We have refined our objective to incorporate our 
refined primary outcome (see Primary Outcome 
Measures below). The intent of this work was always 
to assess access to kidney transplant and with the 
availability of new datasets we can now do this in a 
refined way. Our outcome now captures the complete 
patient journey in access to kidney transplant.   
We changed the term “renal program” to “chronic 
kidney disease program” or “CKD program” to align 
with the terminology used in our published trial 
protocol and to align with the nomenclature used by 
the Ontario Renal Network (part of Ontario Health) 
when it refers to the programs. To keep consistent 
with our published trial protocol we have changed the 
term “standard of care” to “usual care”. 
Study start date 
March 3, 2017 
Changed from: Half of the chronic kidney disease programs will receive 
the multicomponent quality improvement program early (Fall 2017). 
Changed to: Provided the exact start date for the trial (November 1, 
2017). 
We always planned for the trial to start in Fall 2017 
with the original goal of it starting in September 2017. 
However, after randomization we learned that the 
chronic kidney disease programs were not ready to 
start the trial until November 2017. Therefore, in our 

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published protocol we describe the rationale for a 9-
month lead time being given after randomization to 
give the intervention group enough time to establish 
their quality improvement teams and to manage 
schedules so team members could attend the in-
person quality improvement launch event at the start 
of the trial period.  
Study Status  
February 24, 2020 
 
 
 
 
 
 
 
December 4, 2020 
Study status revision 1: 
Changed from: Estimated Primary Completion Date: November 2019 
Estimated Study Completion Date: November 2019 
Changed to:  Estimated Primary Completion Date: March 31, 2021 
Estimated Study Completion Date: March 31, 2021 
 
 
 
Study status revision 2: 
Changed from: Estimated Primary Completion Date: March 31, 2021 
Estimated Study Completion Date: March 31, 2021 
Changed to: Estimated Primary Completion Date: December 31, 2021 
Estimated Study Completion Date: December 31, 2021 
 
 
 
 
Study status revision 1:  
We increased the length of the trial to improve 
statistical power (please see power section). This will 
allow a better understanding of whether the multi-
component quality improvement intervention had an 
impact on increasing access to kidney transplantation 
in Ontario. 
 
Study status revision 2: 
On March 16, 2020 nearly all kidney transplants and 
evaluations for deceased and living donor transplants 
were suspended in Ontario due to the COVID-19 
pandemic. Similarly, most components of the multi-
component quality improvement intervention were 
halted. The four components of the intervention 
started ramping up again in September 2020 and 
transplant activity started increasing in June 2020 but 
did not return to full capacity for several months. 
Extending the length of time of the multi-component 
quality improvement intervention in the first arm will 
allow adequate time for CKD programs to be exposed 
to the intervention when it is functioning at its full 
potential.  
Study Follow-up 
Period 
February 24, 2020 
 
 
 
December 4, 2020 
 
Study follow-up period revision 1: 
Changed from: 2 years 
Changed to: 3.4 years 
Study follow-up period revision 2: 
Changed from: 3.4 years 
Please see study status section above for rationale of 
study follow-up period revision 1 and 2. 
 
 
 
 

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June 23, 2022 
Changed to: 4.1 years 
Added clarification: 
Changed from: 4.1 years 
Changed to:4.17 years. 
 
No change was made to the study follow-up period. 
We simply are providing a more precise time frame 
and this precise time frame aligns with our published 
statistical analysis plan. 
Arm  
August 10, 2020 
Changed from: Arm title (experimental arm): Multicomponent Initiative 
Arm description: A number of quality improvement initiatives will be 
provided at the CKD programs. 
Changed to: Arm title (experimental arm): Multi-component quality 
improvement intervention 
Arm description: A multi-component quality improvement intervention 
will be provided at chronic kidney disease (CKD) programs. 
 
Change from: Arm title (no intervention): Routine Care/standard-of-care 
Changed to: Arm title (no intervention): Usual Care 
No changes to the intervention were made. The 
change was made to make the terminology consistent 
with the published trial protocol. 
 
 
 
 
 
No changes in the delivery of care were made to the 
no intervention group. We changed the terminology 
to “usual care” to reflect the terminology used in our 
published trial protocol. 
Intervention  
August 10, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Changed from: Intervention name: Multi-component Initiative 
Changed to: Intervention name: Multi-component quality improvement 
intervention 
 
Changed from: Intervention description: The initiative is grounded in a 
quality improvement framework and has four main components for the 
chronic kidney disease (CKD) programs, including:   1. Data (e.g., data 
collection and reports to CKD programs about their performance using 
best practices in audit and feedback); 2. Education (e.g., education 
toolkits for CKD program staff, renal patients and families, including living 
donor candidates); 3. Transplant Ambassadors (e.g., kidney transplant 
recipients and living kidney donors who discuss transplantation and living 
donation to patients and their families) and 4. Administration (e.g., 
provincial administrative support and resources provided to CKD 
programs to support local work). 
Changed to: Intervention description:  The multi-component quality 
improvement intervention has four main components for the chronic 
kidney disease programs: (1) local quality improvement teams and 
The four main trial components and their delivery 
have not changed; we have simply refined how we 
describe these components. Please refer to our 
published trial protocol and published statistical 
analysis plan for further details on each of the 
intervention components. 
 

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administrative support; (2) tailored education and resources for staff, 
patients, and living kidney donor candidates; (3) support from kidney 
transplant recipients and living kidney donors; and (4) program-level 
performance reports and oversight by program leaders.   
 
Added clarification: Intervention description (Only the wording of the first 
component changed and the wording of all other components stayed the 
same): (1) support for local quality improvement teams and 
administrative needs.  
Primary 
Outcome 
Measures 
November 19, 
2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
June 23, 2022 
 
 
 
Changed from: Primary Outcome: Composite outcome of living kidney 
donor candidate referral and transplant recipient referral event rate.  
Description: The primary outcome has not been finalized. It will be 
finalized well before the trial ends and before the analysis of results. The 
outcome will be published in the peer-reviewed protocol. 
Time Frame: Two years 
 
Changed to: Primary Outcome: Number of key steps completed towards 
receiving a kidney transplant. 
Description: The average number of key steps completed towards 
receiving a kidney transplant per 100 person-years during the trial period 
and analyzed at the cluster-level (chronic kidney disease program). Each 
step will only be counted once per patient (the first time it occurs), and 
each patient can contribute a maximum of four steps to their group total. 
The four steps include: Step I: patient referred to a transplant centre for 
evaluation, Step II: at least one living kidney donor candidate contacts a 
transplant centre for an intended recipient and completes a health history 
questionnaire to begin their evaluation, Step III: patient added to the 
deceased donor transplant wait list, and Step IV: patient receives a kidney 
transplant from a living or deceased donor. Patients who complete steps 
before the trial starts can contribute new steps during the trial period. 
Time Frame: 4.1 years 
 
Added Clarification:  Primary Outcome: Completing key steps toward 
receiving a kidney transplant 
Description: The primary outcome is completing key steps toward 
receiving a kidney transplant, where up to 4 unique steps 
Please see the “Objective” section above first for 
further explanation for the outcome being refined. 
The primary outcome was refined based on our 
analysis of historic records. The intent of this work is 
to test an intervention to improve access to kidney 
transplant and with the availability of new datasets 
this can now be done in a refined way. The four steps 
that comprise the primary outcome are key steps to 
receiving a kidney transplant. This outcome now 
captures the complete patient journey in access to 
transplant.  
 
 
 
 
 
 
 
 
 
 
 
 
No change was made to the primary outcome we 
simply improved the wording to make it more easily 
understood by the reader. Please refer to the Analysis 
of Trial Outcomes section of this table for a rational 

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per patient will be considered: (1) patient referred to a transplant center 
for evaluation, (2) a potential living kidney donor begins their evaluation 
at a transplant center to donate a kidney to the patient, (3) patient added 
to the deceased donor transplant wait list, and (4) patient receives a 
kidney transplant from a living or deceased donor.  A patient-level 
analysis will be used to determine the intervention effect on completed 
key steps towards receiving a kidney transplant. 
Time Frame: 4.17 years 
for the change from a cluster-level analysis to a 
patient-level analysis.  
Secondary 
Outcome 
Measures 
June 24, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Changed from:  
1. Kidney transplantation rate (living and deceased donor kidney 
transplants examined separately and together)  
Description: The secondary outcome has not been finalized. It 
will be finalized well before the trial ends and before the analysis 
of results. The outcome will be published in the peer-reviewed 
protocol. 
Time Frame: Two years  
2. Rate of pre-emptive kidney transplantation  
Description: The secondary outcome has not been finalized. It 
will be finalized well before the trial ends and before the analysis 
of results. The outcome will be published in the peer-reviewed 
protocol. 
Time Frame: Two years  
3.  Rate of kidney transplant waitlisting  
Description: The secondary outcome has not been finalized. It 
will be finalized well before the trial ends and before the analysis 
of results. The outcome will be published in the peer-reviewed 
protocol. 
Time Frame: Two years 
4.  Average Healthcare Costs   
Description: The secondary outcome has not been finalized. It 
will be finalized well before the trial ends and before the analysis 
of results. The outcome will be published in the peer-reviewed 
protocol. 
Time Frame: Two years 
The average wait time for a deceased donor kidney 
transplant is approximately five years in Ontario, 
therefore, we hypothesize that the intervention is 
likely to have only a small impact on the rate of 
deceased donor kidney transplants. For this reason, 
five secondary outcomes have been pre-specified to 
examine the impact of the intervention on the rate of 
living kidney donor activity.  
 
 
 
 
 
 
 
 
 
 

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Changed to: We have pre-specified five secondary outcomes to examine 
the impact of our intervention on living kidney donor activity.   
1.  A living donor candidate contacts a transplant centre for a 
patient and completes a health history questionnaire to begin 
their evaluation or a patient receives a living donor transplant.  
Description: Given that the average wait time for a deceased 
donor kidney transplant is five years on average in Ontario, our 
intervention is likely to have only a small impact on the rate of 
deceased donor kidney transplants. For this reason, we have pre-
specified five secondary outcomes to examine the impact of our 
intervention on the rate of living kidney donor transplant 
activity. 
                Time Frame: 4.1 Years  
2. A living kidney donor candidate contacts a transplant centre for a 
patient and completes a health history questionnaire to begin 
their evaluation. 
Description: Secondary outcome selected to examine the rate of 
living kidney donor transplant activity. 
                Time Frame: 4.1 Years 
3. A transplant centre receives a patient’s complete referral 
package from a chronic kidney disease program and a living 
kidney donor candidate contacts a transplant centre for a patient 
and completes a health history questionnaire to begin their 
evaluation.   
Description: Secondary outcome selected to examine the rate of 
living kidney donor transplant activity. 
                Time Frame: 4.1 Years 
4.  A patient receives a living donor kidney transplant.  
Description: Secondary outcome selected to examine the rate of 
living kidney donor transplant activity. 
                 Time Frame: 4.1 Years 
5.  Pre-emptive living donor kidney transplants  
 Description: Secondary outcome selected to examine the rate of 
living kidney donor transplant activity. This outcome is restricted 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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June 23, 2022 
 
 
 
 
 
 
to patients who were not receiving dialysis when they entered 
the trial and not on dialysis at the time of transplant. 
              Time Frame: 4.1 Years 
 
Added Clarification:  
1. A potential living kidney donor begins their evaluation at a 
transplant centre to donate a kidney to the patient and/or a 
patient receives a living donor transplant. 
Description: Given that the average wait time for a deceased 
donor kidney transplant is five years on average in Ontario, our 
intervention is likely to have only a small impact on the rate of 
deceased donor kidney transplants. For this reason, we have pre-
specified five secondary outcomes to examine the impact of our 
intervention on living kidney donor transplant activity. 
 Time Frame: 4.17 Years 
2. Time to first occurrence of a potential living kidney donor 
beginning their evaluation at a transplant centre to donate a 
kidney to the patient. 
Description: Secondary outcome selected to understand living 
kidney donor transplant activity. 
 Time Frame: 4.17 Years 
3. A transplant centre receives a patient’s complete referral 
package from a chronic kidney disease program and at least one 
potential living kidney donor begins their evaluation at a 
transplant centre to donate a kidney to the patient. 
Description: Secondary outcome selected to understand living 
kidney donor transplant activity. 
                Time Frame: 4.17 Years 
4. A patient receives a living donor kidney transplant. 
Description: Secondary outcome selected to understand living 
kidney donor transplant activity. 
Time Frame: 4.17 Years 
 
 
 
All secondary outcomes were listed in our original 
published protocol. No secondary outcomes where 
changed. We now provide additional details as we 
thought that the interpretation could be subjective.  
Please refer to our published statistical analysis plan 
for further details. No change was made to the time 
frame. We simply are providing a more precise time 
frame and this precise time frame aligns exactly with 
our published statistical analysis plan. 

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5. Pre-emptive living donor kidney transplants (restricted to 
patients who were not receiving dialysis when they entered the 
trial and not on dialysis at the time of transplant). 
Description: Secondary outcome selected to understand living 
kidney donor transplant activity. 
Time Frame: 4.17 Years 
Other pre-
specified 
outcomes  
August 7, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Added:  We will consider several other outcomes in an exploratory 
analysis. Other outcome measures, include:  
1. Rate of deceased donor kidney transplant   
Description: Rate of deceased donor kidney transplant censoring 
at death and receipt of a living donor kidney transplant. 
Time Frame: 4.1 Years 
2. Average number of months from the date of dialysis initiation 
(i.e. trial entry) to the date of referral. 
Description: This outcome is assessed in patients receiving 
maintenance dialysis who were referred to a transplant centre. 
Time Frame: 4.1 Years 
3. Rate of living kidney donor transplants  
Description: This outcome is assessed in patients waitlisted for a 
deceased donor kidney transplant and censored at death and 
receipt of a deceased donor kidney transplant. 
Time Frame: 4.1 Years 
4. Proportion of pre-emptive transplants  
Description: This outcome is assessed in recipients of a living 
kidney donor transplant and restricted to patients who were not 
receiving dialysis when they entered the trial and not on dialysis 
at the time of transplant. 
Time Frame: 4.1 Years 
5. Average number of months from the date of referral to a 
transplant centre to the date the first living donor candidate 
contacts the transplant centre for the intended recipient  
Description: This outcome is assessed in recipients of a living 
kidney donor transplant. 
All other outcomes provide additional important 
information about access to kidney transplant. Further 
details on these measures can be found in our 
published trial protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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March 9, 2023 
Time Frame: 4.1 Years 
6. Average number of months from the date of referral to a 
transplant centre to date of the transplant surgery 
Description: This outcome is assessed in recipients of a living or 
deceased donor kidney transplant. 
Time Frame: 4.1 Years 
Added Clarification: 
1. Rate of deceased donor kidney transplant   
Description: Rate of deceased donor kidney transplant censoring 
at receipt of a living donor kidney transplant and at the censoring 
events included in the main trial analysis (i.e., emigration, trial 
end date [December 31, 2021], death, evidence of recovered 
kidney function, or on the date a recorded contraindication to 
transplant occurs [with the exception of age >75]). 
3. Rate of living kidney donor transplants  
Description: This outcome is assessed in patients waitlisted for a 
deceased donor kidney transplant and censored at receipt of a 
deceased donor kidney transplant and at the censoring events 
included in the main trial analysis (i.e., emigration, trial end date 
[December 31, 2021], death, evidence of recovered kidney 
function, or on the date a recorded contraindication to 
transplant occurs [with the exception of age >75]). 
Changed from: 4.1 years 
Changed to:4.17 years 
 
 
Removed: 
• 
Rate of living kidney donor transplants assessed in patients 
waitlisted for a deceased donor kidney transplant 
 
 
 
 
 
 
 
No change was made to these outcomes. We are just 
providing more clarification on the censoring events. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No change was made to the time frame. We simply 
are providing a more precise time frame and this 
precise time frame aligns exactly with our published 
statistical analysis plan. 
 
This measure was listed in the protocol but was not 
analyzed because there was concern that the measure 
would not provide meaningful information. 
Balancing 
Measures 
August 7, 2020 
 
 
 
 
Added: Balancing Measures 
• 
Proportion of patient referrals to a transplant centre where the 
referral was declined. 
We added balancing measures to track whether our 
multi-component quality improvement intervention, 
which was designed to improve access to transplant, 
did not inadvertently introduce problems in other 

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• 
Proportion of patient referrals to a transplant centre where the 
referral information was incomplete (e.g. missing diagnostics 
and/or other required patient information). 
• 
Proportion of patient referrals to a transplant centre where the 
referral was deferred. 
• 
Proportion of patient referrals to a transplant centre where the 
referral was accepted. 
• 
Proportion of patients referred to a transplant centre who were 
not waitlisted or transplanted within 1-year of referral. 
• 
Average time from patient referral to transplant centre to 
consulting with a transplant nephrologist (restricted to patients 
who had a referral that was accepted).  
• 
Average time from referral to transplant centre to being 
waitlisted (restricted to patients who were waitlisted). 
• 
Average time from consulting with a transplant nephrologist to 
being waitlisted (restricted to patients who were waitlisted). 
• 
Average time from referral to living kidney donor 
transplantation. 
• 
The proportion of living donor candidates who complete all the 
following: a nephrology consultation, a surgeon consultation, 
and a computed tomography angiogram. 
• 
Average time from completing the health history questionnaire 
to the computed tomography angiogram. 
• 
Average time from completing the health history questionnaire 
to donor nephrectomy. 
• 
Average time from nephrologist consultation to donor 
nephrectomy. 
Removed: 
• 
Proportion of patient referrals to a transplant centre where the 
referral information was incomplete. 
• 
Average time from patient referral to transplant centre to 
consulting with a transplant nephrologist (this measure could 
also be restricted to patients who received a living kidney donor 
transplant during the trial period). 
aspects of care. Further details on balancing measures 
are described in our published trial protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
These measures were listed in the protocol but were 
not analyzed because either the data were of 
insufficient quality or there was concern that the 
measure would not provide meaningful information. 
The published trial protocol indicated some of the 
balancing measures would be reported during the trial 
period, while others would be assessed as a change 
from historical norms pre-dating the trial. For reasons 

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• 
Average time from consulting with a transplant nephrologist to 
being waitlisted (this measure could also be restricted to 
patients who received a living kidney donor transplant during the 
trial period). 
• 
Average time from referral to transplant centre to being 
waitlisted for patients who received a living kidney donor 
transplant during the trial period. 
• 
The proportion of living donor candidates who complete all the 
following: a nephrology consultation, a surgeon consultation, 
and a computed tomography angiogram. 
• 
Average time from completing the health history questionnaire 
to the computed tomography angiogram, restricted to those 
who ultimately received a living kidney transplant during the 
trial. 
• 
Average time from nephrologist consultation to donor 
nephrectomy. 
of time, cost, and feasibility we focused on reporting 
these measures by group only during the trial period. 
Statistical 
Significance 
December 5, 2019 
Added: To avoid type I errors due to multiple comparisons, we will use 
the fixed-sequence procedure, a stepwise multiple-testing procedure 
where two-sided hypothesis tests for superiority will be performed at the 
0.05 significance level in a pre-specified order. We will test the primary 
outcome first. This will be followed by the five secondary outcomes. Once 
a hypothesis test is not significant, no further testing will be done. Rather, 
the analyses of any subsequent secondary outcomes, as well as additional 
outcomes and other analyses will be reported as point estimates with 
95% confidence intervals (without p values); we will indicate that interval 
widths are not adjusted for multiple testing and therefore inferences 
drawn may not be reproducible. 
 
 
 
During the course of our trial newly recommended 
guidance was published to avoid Type 1 errors due to 
multiple comparisons.1,2,3 To avoid type I errors due to 
multiple comparisons we will use the fixed-sequence 
procedure, a stepwise multiple-testing procedure. 
 
1. Harrington D, D’Agostino RB, Gatsonis C, et al. New 
Guidelines for Statistical 
Reporting in the Journal. N Engl J Med. 
2019;381(3):285-286. doi:10.1056/NEJMe1906559 
2. U.S. Department of Health and Human Services, 
Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER). Multiple 
Endpoints in Clinical Trials: Guidance for Industry. 
Silver Spring, MD; 2017. 
3. Massachusetts Medical Society. Submitting to NEJM 
- Statistical Reporting Guidelines. 

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manuscripts. Accessed December 4, 2019. 
Statistical Power  
August 10, 2020 
Added:  Statistical power calculations for the primary outcome (the 
number of steps completed towards receiving a kidney transplant) were 
informed by an analysis of historical administrative healthcare data in 
Ontario (from November 1, 2016 to October 31, 2017). We estimate a 3.5 
year trial should have at least 80% power to detect a rate ratio of 1.5 (this 
corresponds to patients in the intervention group completing an average 
of 12 more steps per 100 person-years than patients in the control group 
[35 steps vs. 23 steps, respectively]; 2-sided α=0.05).  
At the beginning of the trial the only way we could get 
power estimates was through conducting a literature 
review. However, a much more refined way to 
calculate power is to use historic transplant data that 
became available to us. Specifically, we could analyze 
historic data and get event rates which in turn 
informed our power calculations. See our published 
trial protocol for further details on our statistical 
power calculations. 
Cohort Selection 
August 10, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
June 23, 2022 
 
 
 
 
 
 
 
 
 
Added: The primary analysis will be focused on individuals in multi-care 
kidney clinics (provide care to patients with kidney disease approaching 
the need for dialysis) or in dialysis programs with no recorded 
contraindications to kidney transplant in ICES administrative healthcare 
databases (i.e. patients that are eligible for transplant). Examples of 
recorded contraindications to transplant include dementia, use of home 
oxygen, living in a long-term care home, and any comorbidities likely to 
preclude transplantation. We will also restrict our primary analysis to 
individuals aged 18 to 80 as few people over age 80 are healthy enough to 
receive a transplant. Additional details can be found in our published trial 
protocol. We will also exclude patients from our analysis with invalid or 
missing data on date of birth or sex, and patients who are not permanent 
residents of Ontario (<1% will be excluded for a reason of invalid or 
missing data). 
Changed from: Although older age is not an absolute contraindication to 
transplant, few people over age 80 are healthy enough to receive a 
transplant, and transplants in this age group are rare in Ontario; we will 
therefore exclude those ≥80 years of age. Additional exclusion criteria 
include evidence of any recorded contraindications to transplant 
including dementia, use of home oxygen (a sign of serious pulmonary 
disease), living in a long-term care home, and any comorbidities likely to 
preclude transplantation. 
Changed to: We found that >97% of patients with one or more of the 
following characteristics did not receive a transplant in follow-up, and so 
Although the analysis will be restricted to individuals 
approaching the need for dialysis or patients on 
dialysis with no recorded contraindications to 
transplant, the delivery of the intervention is at the 
CKD program level and all CKD programs in Ontario 
are included. At the time of the final analysis, pre-
specified selection criteria will be applied to restrict 
the statistical analysis to the patients of interest for 
trial inclusion. 
 
 
 
 
 
We further refined our eligibility criteria based on an 
analysis we conducted where we compared 80+ 
baseline characteristics between patients who did and 
did not receive a kidney transplant during follow-up.1 
We also further refined our eligibility criteria to 
exclude individuals receiving conservative renal care; 
these individuals would not be eligible to receive a 
kidney transplant as they have opted for conservative 
care to manage their kidney disease.  Conservative 
renal care is a new variable available in our 

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patients with these characteristics will not enter the trial for analysis: an 
ESKD adapted Charlson comorbidity index score ≥7 (a higher score 
represents greater comorbidity), age >75 years, home oxygen use, 
dementia, living in a long-term care facility, receiving ≥1 physician house 
call in the past year, or any of the following cancers: bladder, cervical, 
colorectal, liver, lung, lymphoma, or active multiple myeloma. We have 
also clarified that receiving conservative renal care will be considered a 
contraindication to transplant as these patients have decided not to purse 
dialysis or transplantation. 
Added clarification: In our published statistical analysis plan we specified 
that we are using the 2021 Chronic Kidney Disease–Epidemiology 
Collaboration Equation, without race, to calculate the estimate 
glomerular filtration rate. 
Added clarification: In our published statistical analysis plan we included 
details on our cohort selection stating, “to ensure stability of kidney 
function, at least two eGFR or two KFRE measures were required to enter 
the cohort and these measures had to be separated by at least >90 days 
but within 365 days.” 
administrative databases which we did not have 
access to when we wrote our original protocol. 
Reference: 
1. Wang C, Naylor KL, Luo B, et al. Using 
Administrative Health Care Databases to 
Identify Patients With End-Stage Kidney 
Disease With No Recorded Contraindication 
to Receiving a Kidney Transplant. CJKHD 2022 
Jul 21;9:1-14. 
 
No change was made. We simply provided clarification 
on the equation that we will use to calculate the 
estimated glomerular filtration rate.  
 
No changes were made. We are simply providing more 
details. 
Eligibility (as 
described on 
ClinicalTrials.gov)  
August 10, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Changed from: Eligibility Criteria: This is a pragmatic cluster randomized 
controlled trial with eligibility criteria detailed below.  
Inclusion Criteria: 
•All 26 chronic kidney disease (CKD) programs in Ontario. These programs 
provide care for all chronic dialysis patients in the province. Each CKD 
program also provides a multi-care kidney clinic for patients with 
advanced CKD who are progressing to end-stage renal disease. 
Changed to: Eligibility Criteria: This is a pragmatic, two-arm, parallel-
group, open-label, registry-based cluster randomized clinical trial with 
eligibility criteria detailed below. 
Inclusion Criteria: 
•All 26 chronic kidney disease (CKD) programs in Ontario. These programs 
provide care for all chronic dialysis patients in the province. Each CKD 
program also provides a multi-care kidney clinic for patients with 
advanced CKD who are approaching the need for dialysis. 
No changes were made to the eligibility criteria. We 
have just provided more detail on the trial design. In 
the inclusion criteria we also refined the wording to 
indicate that CKD programs provide a multi-care 
kidney clinic for patients with advanced CKD who are 
approaching the need for dialysis (previously we said 
progressing to end-stage renal disease). The wording 
now aligns with our published trial protocol.   
 
 
 
 
 
 
 
 

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June 23, 2022 
Added clarification: Eligibility Criteria (only bolded word added): This is a 
pragmatic, two-arm, parallel-group, open-label, registry-based, 
superiority, cluster randomized clinical trial with eligibility criteria 
detailed below. 
No change was made to the design of the trial, rather 
we added the term superiority, to align with the 
wording in our published statistical analysis plan. This 
trial was always a superiority trial. 
Analysis of Trial 
Outcomes 
August 10, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
June 23, 2020 
 
 
 
 
 
 
 
Analysis of trial outcomes revision 1: 
Changed from: To determine if a statistically significant difference in the 
referral rate exists between the multi-component kidney transplant 
quality improvement program and the standard of care group a Poisson 
regression model will be used which includes potential confounders but 
not the intervention status. This method has been found in simulation 
studies to be robust even when there are a small number of clusters and 
when the distribution of cluster sizes is skewed. Study data at ICES will be 
used. 
Changed to: Study data will be obtained from Ontario’s linked 
administrative healthcare databases at ICES (ices.on.ca). We will account 
for the study design and covariate-constrained randomization in our 
analysis. The primary outcome is at the cluster level (the rate of 
completing steps towards receiving a kidney transplant [per 100 person-
years]) and will be compared between groups using a two-stage approach 
because we have 26 clusters randomized (13 per arm). In the first stage of 
the model, residuals are obtained from fitting a regression model to the 
individual level count data adjusting for pre-specified individual-level 
confounders while ignoring the intervention and clustering effects. In the 
second stage, the residuals from the first stage are aggregated at the 
cluster level and used as the outcome to estimate the effect of the 
intervention. This model fits cluster-level variables and the treatment 
effect. 
Analysis of trial outcomes revision 2: 
Changed from the above. 
Changed to: The primary outcome will be analyzed using a patient-level 
constrained multi-state model adjusting for the clustering within CKD 
programs. Bootstrapping at the cluster level will be used to maintain valid 
inference in the presence of correlated outcomes within CKD programs. 
We are interested in the global intervention effect for all completed steps 
towards transplantation. That is, we will be constraining the intervention 
We have refined our analysis based on feedback from 
our study biostatistician and a review of historic 
records. The new adopted statistical method was 
thought to be more appropriate given our updated 
primary outcome and number of clusters within each 
arm. The analysis will still be completed at the cluster 
level and still be done using an intent-to-treat 
approach. Please refer to our published trial protocol 
for more details. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The lead trial statistician, without knowledge of the 
trial results, considered different approaches as it 
pertained to statistical power and changed the 
statistical approach. For several reasons, we changed 
to a patient-level analysis with a multistate statistical 

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Revision 
Date of Revision  
Details of Revision 
Rationale 
 
 
 
 
 
 
 
August 10, 2020 
 
 
 
 
June 23, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
August 10, 2020 
 
effect to be the same for each state transition in our primary analysis. 
This approach will provide a single estimate of the relative rate (i.e., 
hazard ratio) of steps completed towards receiving a transplant among 
patients in CKD programs in the intervention group versus the usual-care 
group. 
 
Changed from: We will censor at death or end of study.  
Changed to: We will follow patients in our analysis until the end of study, 
death, receipt of a kidney transplant, or become ineligible for transplant, 
whichever comes first. 
Added clarification: A patient’s observation time will only stop on the 
trial end date (December 31, 2021), death, receipt of a kidney transplant, 
evidence of recovered kidney function, emigration, or on the date a 
recorded contraindication to transplant occurs (with the exception of age 
>75 years). 
 
 
 
 
 
 
 
 
 
Added: A patient’s follow-up time will begin on November 1, 2017 or on 
the earliest date when all eligibility criteria were met up until 3 months 
before the trial end date (3 months is the expected minimum time to 
complete early steps towards receiving a kidney transplant). Patients can 
only enter the analytic cohort once. 
model, which are fully described in our published 
statistical analysis plan.  
 
 
 
We have refined our censoring events to ensure our 
denominator is capturing the population of interest. 
 
 
 
In our published protocol we indicated that we would 
stop following individuals when they become ineligible 
for transplant. We are also censoring at recovered 
kidney function as these individuals would not be 
actively taking steps towards a transplant. 
We will keep individuals in the trial analysis if they 
turn aged > 75 years during follow-up given they were 
75 years when they entered the trial, and a small 
proportion of older individuals receive a kidney 
transplant. As described in our published statistical 
analysis plan, we will also be censoring at emigration 
from the province using updated methodology 
available using our administrative data sources. 
 
We provide detail on the timeframe for entering the 
analytic cohort for analysis. 
 
 
 
Additional 
exploratory 
analyses 
 
August 10, 2020 
 
 
 
 
Added: We have added pre-specified subgroup analyses. Specifically, in 
additional exploratory analyses we will consider subgroup analyses to 
determine if the intervention improved access to kidney transplant in the 
following subgroups: receiving maintenance dialysis at the time of trial 
entry (in-centre or home dialysis), sex (male vs. female), race (white vs. 
We want to explore the effects of the intervention in 
different subgroups, with a focus on subgroups that 
have traditionally experienced lower access to 
transplant. 
 

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June 23, 2022 
other), immigration status, geography (average distance from the 
patient’s place of residence to the transplant centre), income quintile 
(measured by neighbourhood-level median income), and measures of 
marginalization (i.e. residential instability, material deprivation, ethnic 
concentration, and dependency). 
 
Changed to: We will not perform subgroup analyses of the intervention 
effect by race (white vs. other) or immigration status. 
 
 
 
 
 
 
 
 
 
 
 
Added: In addition to the subgroup analyses described in our published 
protocol, we will also conduct subgroup analyses based on how the 
patient entered the trial (whether patients were approaching the need 
for dialysis or receiving maintenance dialysis as well as if patients entered 
on November 1, 2017 or during the accrual period). 
 
Added Clarification: As specified in our protocol, the primary analysis for 
this trial will not account for pandemic-related changes in transplant 
activity. However, we will conduct an additional analysis in which 
patients’ follow-up times will be truncated on the date transplant activity 
was first suspended in Ontario. We are also conducting a concurrent 
process evaluation using surveys and interviews to understand how the 
intervention was delivered in each CKD program, and we will ask 
respondents how the pandemic affected these activities. 
 
 
 
 
 
 
After consultation with our project partners, we will 
not perform subgroup analyses by race and 
immigration status. We do not have access to self-
reported race which is considered the gold standard 
for determining individuals’ race and ethnicity. 
Ethnicity information in the Ontario Renal Reporting 
System was collected by data leads in each CKD 
program at the time of patient registration, based on 
charting by clinical staff who could ask patients to self-
identify ethnicity but who were not mandated to do 
so. 
 
 
We updated our subgroup analyses by including an 
analysis based on how the patient entered the trial. 
This was always an intended analysis but was not 
explicit in the published protocol. This information is 
detailed in our published statistical analysis plan. 
 
Given the challenges of delivering the intervention 
during the COVID-19 pandemic, we will perform a pre-
specified analysis of our primary and secondary 
outcomes restricting the trial period and follow up 
from November 1st, 2017 to December 20th, 2019 with 
follow up to March 16th, 2020. March 16th, 2020 aligns 
with the suspension of transplant activity in Ontario. It 
is possible any beneficial effect of the intervention will 
be more pronounced in the pre-pandemic period. 
Sponsors and 
Collaborators 
August 10, 2020 
Changed from: Collaborators: 
Institute for Clinical Evaluative Sciences 
We added the Ontario Renal Network as a 
collaborator. The Ontario Renal Network has always 

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Date of Revision  
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Canadian Institutes of Health Research (CIHR) 
Changed to: Collaborators: 
ICES (formerly known as the Institute for Clinical Evaluative Sciences) 
Canadian Institutes of Health Research (CIHR) 
Ontario Renal Network (ORN) (part of Ontario Health) 
Trillium Gift of Life Network (TGLN) (part of Ontario Health) 
been involved with the organization and the delivery 
of the intervention. We are now officially listing them 
to align with our published trial protocol. We also now 
include TGLN as a collaborator.  
 

32 
 
Final statistical analysis plan 
Reference 
Dixon SN, Naylor KL, Yohanna S, McKenzie S, Belenko D, Blake PG, Coghlan C, Cooper R, Elliott L, Getchell 
L, Ki V, Mucsi I, Nesrallah G, Patzer RE, Presseau J, Reich M, Sontrop JM, Treleaven D, Waterman AD, 
Zaltzman J, Garg AX. Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD): 
Statistical Analysis Plan of a Registry-Based, Cluster-Randomized Clinical Trial. Can J Kidney Health Dis. 
2022 Nov 22;9:20543581221131201. doi: 10.1177/20543581221131201.  
 
 

33 
 
Final process evaluation protocol 
 
Reference 
Yohanna S, Wilson M, Naylor KL, Garg AX, Sontrop JM, Belenko D, Elliott L, McKenzie S, Macanovic S, 
Mucsi I, Patzer R, Voronin I, Lui I, Blake PG, Waterman AD, Treleaven D, Presseau J. Protocol for a 
Process Evaluation of the Quality Improvement Intervention to Enhance Access to Kidney 
Transplantation and Living Kidney Donation (EnAKT LKD) Cluster-Randomized Clinical Trial. Can J Kidney 
Health Dis. 2022 Mar 19;9:20543581221084502. doi: 10.1177/20543581221084502.