Safety and Efficacy of Kidney Transplantation in Patients With Aortoiliac Stenosis
Conditions: Aorto-Iliac Arterial Stenosis, Peripheral Arterial Disease, Kidney Transplant Failure
Sponsor: Erasmus Medical Center

 
 
Kidney transplantation & aortoiliac stenosis 
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Official Title: Safety and Efficacy of Kidney 
Transplantation in Patients with Aortoiliac Stenosis 
 
Brief Title: Aortoiliac Stenosis in Kidney 
Transplantation (TASC) 
 
NCT number: NCT06020534 
 
RESEARCH PROTOCOL 
(30 November 2022) 
 
 

 
 
Kidney transplantation & aortoiliac stenosis 
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PROTOCOL TITLE µSafety and Efficacy of Kidney Transplantation in Patients with Aortoiliac 
Stenosis¶ 
 
Protocol ID 
MEC-2017-1039 
Short title 
Kidney transplantation & aortoiliac stenosis 
EudraCT number  
N.A. 
Version 
3.0 
Date 
30-11-2022 
Coordinating 
investigator/project leader 
 
Y. Fang 
y.fang.1@erasmusmc.nl 
Erasmus MC University  Medical Center Rotterdam 
Department of Surgery 
Dr. Molewaterplein 40, 3015GD Rotterdam 
The Netherlands 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
 
 
<Multicenter research: per site> 
Dr. R.C. Minnee 
r.minnee@erasmusmc.nl 
Erasmus MC University Medical Center Rotterdam 
Department of Surgery 
Dr. Molewaterplein 40, 3015GD Rotterdam 
The Netherlands 
N.A. 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Erasmus MC, University Medical Center Rotterdam 
Department of Surgery 
Dr. Molewaterplein 40 
3015 GD Rotterdam, The Netherlands 
Subsidising party 
N.A. 
Independent expert (s) 
N.A. 
Laboratory sites <if applicable> 
N.A. 
Pharmacy <if applicable> 
N.A. 

 
 
Kidney transplantation & aortoiliac stenosis 
 
 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................10 
2. 
OBJECTIVES ................................................................................................................11 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................13 
4.1 
Population (base) ...................................................................................................13 
4.2 
Inclusion criteria .....................................................................................................13 
4.3 
Exclusion criteria ....................................................................................................13 
4.4 
Sample size calculation ..........................................................................................13 
5. 
TREATMENT OF SUBJECTS .......................................................................................14 
5.1 
Investigational product/treatment ............................................................................14 
5.2 
Use of co-intervention (if applicable) ......................................................................14 
5.3 
Escape medication (if applicable) ...........................................................................14 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................15 
6.1 
Name and description of investigational  product(s) ...............................................15 
6.2 
Summary of findings from non-clinical studies ........................................................15 
6.3 
Summary of findings from clinical studies ...............................................................15 
6.4 
Summary of known and potential risks and benefits ...............................................15 
6.5 
Description and justification of route of administration and dosage .........................15 
6.6 
Dosages, dosage modifications and method of administration ...............................15 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................15 
6.8 
Drug accountability .................................................................................................15 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................16 
7.1 
Name and description of non-investigational product(s) .........................................16 
7.2 
Summary of findings from non-clinical studies ........................................................16 
7.3 
Summary of findings from clinical studies ...............................................................16 
7.4 
Summary of known and potential risks and benefits ...............................................16 
7.5 
Description and justification of route of administration and dosage .........................16 
7.6 
Dosages, dosage modifications and method of administration ...............................16 
7.7 
Preparation and labelling of Non Investigational Medicinal Product ........................16 
7.8 
Drug accountability .................................................................................................16 
8. 
METHODS ....................................................................................................................17 
8.1 
Study parameters/endpoints ...................................................................................17 
8.1.1 
Main study parameter/endpoint .......................................................................17 
8.1.2 
Secondary study parameters/endpoints (if applicable) ....................................17 
8.1.3 
Other study parameters (if applicable) .............................................................17 
8.2 
Randomisation, blinding and treatment allocation ..................................................17 
8.3 
Study procedures ...................................................................................................17 
8.4 
Withdrawal of individual subjects ............................................................................17 
8.4.1 
Specific criteria for withdrawal (if applicable) ...................................................17 
8.5 
Replacement of individual subjects after withdrawal ...............................................17 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................17 

 
 
Kidney transplantation & aortoiliac stenosis 
 
 
 
8.7 
Premature termination of the study .........................................................................17 
9. 
SAFETY REPORTING ..................................................................................................18 
9.1 
Temporary halt for reasons of subject safety ..........................................................18 
9.2 
AEs, SAEs and SUSARs ........................................................................................18 
9.2.1 
Adverse events (AEs) ......................................................................................18 
9.2.2 
Serious adverse events (SAEs) .......................................................................18 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................19 
9.3 
Annual safety report ...............................................................................................20 
9.4 
Follow-up of adverse events ...................................................................................21 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ..................................21 
10. 
STATISTICAL ANALYSIS ..........................................................................................22 
10.1 
Primary study parameter(s) ....................................................................................22 
10.2 
Secondary study parameter(s) ...............................................................................22 
10.3 
Other study parameters ..........................................................................................22 
10.4 
Interim analysis (if applicable) ................................................................................22 
11. 
ETHICAL CONSIDERATIONS ...................................................................................23 
11.1 
Regulation statement .............................................................................................23 
11.2 
Recruitment and consent........................................................................................23 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................23 
11.4 
Benefits and risks assessment, group relatedness .................................................23 
11.5 
Compensation for injury .........................................................................................23 
11.6 
Incentives (if applicable) .........................................................................................24 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................25 
12.1 
Handling and storage of data and documents ........................................................25 
12.2 
Monitoring and Quality Assurance ..........................................................................25 
12.3 
Amendments ..........................................................................................................25 
12.4 
Annual progress report ...........................................................................................26 
12.5 
End of study report .................................................................................................26 
12.6 
Public disclosure and publication policy ..................................................................27 
13. 
STRUCTURED RISK ANALYSIS...............................................................................28 
13.1 
Potential issues of concern .....................................................................................28 
13.2 
Synthesis ...............................................................................................................29 
14. 
REFERENCES ..........................................................................................................29 

 
 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; 
in Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-
formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IB 
,QYHVWLJDWRU¶V%URFKXUH 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics; in Dutch: officiële 
productinformatie IB1-tekst 
Sponsor 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; 
in Dutch: Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 

 
 
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SUMMARY 
 
Rationale: Kidney transplantation is the standard treatment for end stage renal disease 
(ESRD). Patients with aortoiliac stenosis are often ineligible for kidney transplantation due to 
the high risk of vascular complications. 
Objective: To assess the impact of pre-transplant aorto-iliac stenosis on short and long term 
outcomes of kidney transplant patients. 
Study design: Single-centre retrospective cohort study 
Study population: Patients who underwent kidney transplantation in Erasmus MC between 
January 2010 and December 2020. 
Intervention (if applicable): NA 
Main study parameters/endpoints: Primary outcome measures are patient survival and 
death-censored graft survival and secondary outcome measures are renal function (such as 
eGFR) and the incidence rate of vascular complications. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: This is a retrospective cohort study and no additional burden or risks will 
be applied to the patients. 

 
 
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1. INTRODUCTION AND RATIONALE 
 
Kidney transplantation has been recognized as the paramount therapy for end stage renal 
disease. It increases the quality of life and survival rate of patients when compared with long-
term hemodialysis(1). For patients who are ineligible for kidney transplantation, peritoneal 
dialysis or hemodialysis is the only alternative option. According to the annual data report of 
2016 from the United States Renal Data System, the overall 5 year survival of hemodialysis 
patients is 41,6% and for peritoneal dialysis 59,4% (2). In comparison to those survival rates, 
the survival rate in patients receiving a deceased-donor kidney transplant was 75,7% and for 
patients receiving a living-donor kidney transplant 84,6%(2). Therefore, kidney 
transplantation should be the first choice of therapy in patients with end stage renal disease. 
There is little known about the proportion of renal transplant candidates who are considered 
ineligible by the transplant center. Kianda et al. investigated that 8% of the referred patients 
were considered ineligible and he described in 44% of the patients aorto-iliac atherosclerosis 
as the only reason (3). Other less frequent reasons for ineligibility in this study were severe 
ischemic heart disease, advanced age, metastatic neoplasia and severe impairment of 
general status or a combination of these factors. This shows that aorto-iliac atherosclerosis is 
the most frequent reason why patients are considered ineligible for kidney transplantation. 
 
There are a number of concerns when considering kidney transplantation in patients with 
aortoiliac atherosclerosis. At first, it may complicate a vascular anastomosis between donor 
renal artery and recipient iliac artery during transplantation, sometimes even requiring a 
YDVFXODUSURFHGXUH6HFRQGO\µVWHDOV\QGURPH¶FDQRFFXUZKHUHE\WKHWUDQVSODQWHGRUJDn 
results in redirection of blood flow from an already vulnerable limb leading to distal ischemia. 
This syndrome has been showed in children undergoing renal transplantation(4). However, 
Northcutt et al. investigated this syndrome in adults and he did not show significantly 
deterioration of ischemia(5). The third concern is the physiologic impact of a complex 
operation on these critically ill patients(6, 7). Finally, a recent study concluded that aortic 
calcification index can progress after transplantation and represent a post-transplant 
cardiovascular event risk factor(8). As a result of these concerns, aorto-iliac atherosclerosis 
is a relative contraindication for kidney transplantation. 
 
Over the years, a few case series and case reports have been published about aorto-iliac 
calcifications in renal transplant patients requiring a vascular procedure(6, 7, 9-18). Those 
case series report very successful short term survival and graft function. However, the impact 
of aorto-iliac calcifications on long term survival in kidney transplant patients remains 
unclear. Because of the poor survival of patients requiring dialysis, broader patient selection 
for kidney transplantation is desirable. The present study aims to assess the impact of pre-
transplant aorto-iliac stenosis on short and long term outcomes of the kidney transplant 
patients. 
 

 
 
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2. OBJECTIVES 
 
Primary Objective: This study aims to assess the impact of pre-transplant aorto-iliac stenosis 
on short and long term outcomes of kidney transplant patients. 

 
 
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3. STUDY DESIGN 
 
This single-center retrospective study includes all kidney transplant patients who underwent 
kidney transplantation in Erasmus MC between 2010 and 2020. Data of patient 
characteristics, operation details and long-term outcomes will be collected. All patients will be 
divided into non-stenosis group and stenosis group based on the existence of pre-transplant 
aortoiliac stenosis. Propensity score matching will be used to make the baseline 
characteristics comparable between two groups. Patient survival, graft survival and long-term 
renal function of the two groups will be compared to indicate if the aortoiliac stenosis has an 
impact on the survival of transplant patients. 

 
 
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4. STUDY POPULATION 
4.1 Population (base)  
The research population are patients (n= ~2000) who underwent kidney transplantation in 
Erasmus MC between Jan 2010 and December 2020. Based on the pre-transplant 
existence of aortoiliac stenosis, all patients will be divided into non-stenosis group 
(n=~1800) and stenosis group (n=~120). 
 
4.2 Inclusion criteria 
Patients who underwent kidney transplantation in Erasmus MC between Jan 2010 and 
December 2020 will be included in the study. 
 
4.3 Exclusion criteria 
Patients under 18 years old and who underwent combined kidney and liver transplantation 
will be excluded from the study. 
 
4.4 Sample size calculation 
Sample size calculation is performed by G*Power for future use of t test. Both the 
accepted false positive and negative rate is 5%. The results indicate the sample size 
should be at least 105 in each group to reach a reliable answer, which is feasible based 
on the current patient population. 
  
The protocol of power analyses are as follows: 
Analysis:   A priori: Compute required sample size  
Input:        Tail(s)                          =      Two 
                 Effect size d                             =      0,5 
                 ĮHUUSURE          =      0,05 
                 Power (1-ȕHUUSURE   =      0,95 
                 Allocation ratio N2/N1              =      1 
Output:     NRQFHQWUDOLW\SDUDPHWHUį=      3,6228442 
                 Critical t                                   =      1,9714347 
                 Df                                            =      208 
                 Sample size group 1               =      105 
                 Sample size group 2               =      105 
                 Total sample size                   =      210 
                 Actual power                           =      0,9501287 

 
 
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5. TREATMENT OF SUBJECTS 
      NA 
 
5.1 Investigational product/treatment 
<Please give a description of the intervention (medicinal product, medical device, food 
supplement, radiation, surgery, behavioural interventions, etcetera). Also use of 
comparator or placebo should be described.>  
5.2 Use of co-intervention (if applicable) 
< Please describe what subjects should do and not do (e.g. use co-medication, adequate 
contraception, diet). If it is allowed to use co-medication or other kind of intervention, it 
should be specified on forehand what is allowed.)> 
5.3 Escape medication (if applicable) 
<Please describe type, dose per unit and maximum dose allowed.>  

 
 
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6. INVESTIGATIONAL PRODUCT  
     NA 
  
6.1 Name and description of investigational  product(s) 
6.2 Summary of findings from non-clinical studies 
<One may UHIHUWRWKH,QYHVWLJDWRU¶V%URFKXUH,%,QYHVWLJDWLRQDO0HGLFLQDO3URGXFW
Dossier (IMPD), Summary of Product Characteristics (SPC) or a similar document (if 
applicable), by mentioning the relevant pages in that document. Be sure that the 
information is up to date and references to peer reviewed papers in (biomedical/scientific) 
journals should be given where appropriate.> 
 
6.3 Summary of findings from clinical studies 
<See explanatory text of chapter 6.2, including remark> 
6.4 Summary of known and potential risks and benefits 
<See explanatory text of chapter 6.2, including remark> 
6.5 Description and justification of route of administration and dosage 
6.6 Dosages, dosage modifications and method of administration 
6.7 Preparation and labelling of Investigational Medicinal Product 
 
 
6.8 Drug accountability 
<Please describe the procedures for the shipment, receipt, disposition, return and 
destruction of the investigational medicinal products.> 
 

 
 
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7. NON-INVESTIGATIONAL PRODUCT 
     NA 
  
7.1 Name and description of non-investigational product(s) 
7.2 Summary of findings from non-clinical studies 
<One may UHIHUWRWKH,QYHVWLJDWRU¶V%URFKXUH,%,QYHVWLJDWLRQDO0HGLFLQDO3URGXFW
Dossier (IMPD), Summary of Product Characteristics (SPC) or a similar document (if 
applicable), by mentioning the relevant pages in that document. Be sure that the 
information is up to date and references to peer reviewed papers in (biomedical/scientific) 
journals should be given where appropriate.> 
 
7.3 Summary of findings from clinical studies 
<See explanatory text of chapter 7.2, including remark> 
7.4 Summary of known and potential risks and benefits 
<See explanatory text of chapter 7.2, including remark> 
7.5 Description and justification of route of administration and dosage 
 
7.6 Dosages, dosage modifications and method of administration 
 
7.7 Preparation and labelling of Non Investigational Medicinal Product 
 
7.8 Drug accountability 
<Please describe the procedures for the shipment, receipt, disposition, return and 
destruction of the non-investigational medicinal products.> 
 

 
 
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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
Primary outcome measures are patient survival and death-censored graft survival. 
8.1.2 Secondary study parameters/endpoints (if applicable) 
Secondary outcome measures are renal function (such as eGFR) and vascular 
complications. 
8.1.3 Other study parameters (if applicable) 
NA 
 
 
8.2 Randomisation, blinding and treatment allocation 
NA 
 
8.3 Study procedures 
Since this study is a retrospective study, no additional procedures/tests will be 
performed. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. 
8.4.1 Specific criteria for withdrawal (if applicable) 
8.5 Replacement of individual subjects after withdrawal 
8.6 Follow-up of subjects withdrawn from treatment 
8.7 Premature termination of the study 
< Please describe the criteria for terminating the study prematurely and the 
procedures in case the study will be terminated prematurely.>  
 
 

 
 
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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety.  The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to [the investigational product / 
trial procedure/ the experimental intervention]. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be 
recorded. 
 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
UHTXLUHVKRVSLWDOLVDWLRQRUSURORQJDWLRQRIH[LVWLQJLQSDWLHQWV¶KRVSLWDOLVDWLRQ 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
< Please describe the procedures for handling the serious adverse events. If 
certain SAEs do not require immediate reporting by the investigator to the sponsor, 
please specify.>  
The investigator will report all SAEs to the sponsor without undue delay after 
obtaining knowledge of the events, except for the following SAEs:  <specify which 

 
 
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SAEs do not require immediate reporting by the investigator to the sponsor, if 
applicable>        . 
 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 7 days of first knowledge for 
SAEs that result in death or are life threatening followed by a period of maximum of 8 
days to complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events. 
 
< If certain SAEs do not require( expedited) reporting to the accredited METC, please 
specify these SAEs as well as the frequency of reporting of these SAEs in line 
listings, or in a annual safety report or otherwise.> 
 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
<This chapter is only applicable for studies with an investigational medicinal product> 
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
- 
,QYHVWLJDWRU¶V%URFKXUH for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline  to the METC  <reporting via webportalToetsingOnline is only 
applicable for investigator initiated studies>: 
 SUSARs that have arisen in the clinical trial that was assessed by the METC; 

 
 
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 SUSARs that have arisen in other clinical trials of the same sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be 
submitted once every half year to the METC. This line-listing provides an overview 
of all SUSARs from the study medicine, accompanied by a brief report highlighting 
the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or 
ToetsingOnline is sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first 
knowledge of the adverse reactions. For fatal or life threatening cases the term will 
be maximal 7 days for a preliminary report with another 8 days for completion of the 
report.  
 
< For multicentre studies the responsibilities of investigators in participating centres 
as well as of the coordinating investigator should be clearly defined> 
 
<Please describe also the method of breaking the code for SUSAR reporting.> 
 
9.3 Annual safety report 
 
<This chapter is only applicable for studies with an investigational medicinal product> 
< The annual safety report may be combined with the annual progress report (see chapter 
12.4).> 
 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 

 
 
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 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the 
protocol  
 
9.5 [Data Safety Monitoring Board (DSMB) / Safety Committee] 
<In case a DSMB is established to perform ongoing safety surveillance and to perform 
interim analyses on the safety data, this committee should be an independent committee. 
The composition of the DSMB should be described and it should be clear that each 
member has no conflict of interest with the sponsor of the study. 
The task and responsibility of the DSMB should be described (see chapter 10.4 for interim 
analyses either for safety or for futility or positive efficacy) >  
 
<Criteria on which the DSMB may decide to terminate the trial prematurely should be 
clearly defined before the trial has started.> 
 
The advice(s) of the DSMB will only be sent to the sponsor of the study. Should the 
sponsor decide not to fully implement the advice of the DSMB, the sponsor will send the 
advice to the reviewing METC, including a note to substantiate why (part of) the advice of 
the DSMB will not be followed. 
 
< In case a DSMB is not needed, but some safety review is deemed appropriate, 
information on this safety committee should be given here. Information should be provided 
on the composition of the committee and (in)dependence of the members, the reason to 
establish this committee, type of data that will be reviewed and moment of review, 
possible measures to be taken> 

 
 
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10. STATISTICAL ANALYSIS 
Patient survival, death-censored graft survival and eGFR will be reported as mean ± 
standard deviation (SD) if normally distributed or median with interquartile range (IQR) if 
data is skewed. Categorical variables such as the incidence rate of vascular 
complications will be described as numbers and percentages. Continuous variables will 
EHFRPSDUHGXVLQJVWXGHQW¶VW-test or Mann±Whitney U test. Categorical variables will be 
FRPSDUHGXVLQJȤWHVWRU)LVKHU
VH[DFWWHVW.DSODQ-Meier curves and log-rank test will 
be used to compare patient and graft survival. The data will be analyzed is SPSS. A p-
value of < 0.05 is considered statistically significant. 
 
10.1 Primary study parameter(s) 
Patient survival is defined as the time from transplantation to death or the last follow-up. 
Death-censored graft survival is defined as the time from transplantation to graft failure or 
the last follow-up with a functioning graft, with censoring death with a functioning graft. 
 
10.2 Secondary study parameter(s)  
Data of eGFR will be extracted from Clinical Chemistry department of Erasmus MC. 
Vascular complications are defined as the occurrence of steal syndrome, renal artery 
haemorrhage and thrombosis. 
 
10.3 Other study parameters 
 
 
10.4 Interim analysis (if applicable) 
< Please describe when the interim analysis will be done, which statistical methods will 
be used, who will perform the interim analysis and the stopping rules (if applicable). Also 
refer to the DSMB Charter in case a Data Safety Monitoring Board will be established to 
advice on stopping, see also chapter 9.5> 

 
 
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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki 
(64th WMA General Assembly, Fortaleza, Brazil, October 2013). 
 
11.2 Recruitment and consent 
Gathering the express consent of test subjects is only possible by exerting  
disproportionate effort or would lead to unacceptable selection bias. All allogeneic kidney 
transplantation recipients from 2010 to 2020 are included in this study. The study 
population concerns patients that have been treated 10 years ago; A substantial amount 
of the study population is expected to have passed away and/or has no records available 
about current whereabouts. Asking express consent could result in an unacceptable 
selection bias and therefore produce unreliable data. Recovering addresses would 
involve a disproportionate effort for gathering the express consent of test subjects. The 
Form exception informed consent is attached as a separate document. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
<Please specify which code of conduct is applicable for minors and/or incapacitated 
adults participating in non-therapeutic research. This should also be specified in the 
informed consent letter.>  
 
11.4 Benefits and risks assessment, group relatedness 
<Please give a justification of the proposed study.> 
 
11.5 Compensation for injury 
<Please give information about the liability insurance and the insurance for the subjects 
participating in the study.>  
<The sponsor or investigator should also have a liability insurance.> 
 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of 
the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements 
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to 
research subjects through injury or death caused by the study. 

 
 
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The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 
 
11.6 Incentives (if applicable) 
<Please describe any special incentives, compensation or treatment that subjects will 
receive through participation in the study.> 

 
 
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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
The research data will be pseudonymised by the research coordinator as soon as the first 
record of the participant is created in the research database. The data that is entered in 
the database does not contain any directly identifying data. This way, the identity of the 
subject is only to be re-identified by using the pseudonymisation key. This key is stored 
separately from the data and is managed by the principal investigator. After the project is 
completed, only the principal investigator will have access to the pseudonymisation key 
file. 
 
12.2 Monitoring and Quality Assurance  
< If monitoring of the conduct of the study takes place, please describe who will monitor, 
what will be monitored, frequencies etc. One can refer to a monitoring plan for details > 
 
12.3 Amendments  
<The following text is applicable for studies without an investigational medicinal product.> 
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
<The following text is applicable for studies with an investigational medicinal product.> 
$µVXEVWDQWLDODPHQGPHQW¶LVGHILQHGDVDQDPHQGPHQWWRWKHWHUPVRIWKHMETC 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
 
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.  
< Examples of non-substantial amendments are typing errors and administrative changes 
like changes in names, telephone numbers and other contact details of involved persons 
mentioned in the submitted study documentation.> 

 
 
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12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
<The following text is applicable for studies without an investigational medicinal product.> 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study LVGHILQHGDVWKHODVWSDWLHQW¶VODVWYLVLW  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 
<The following text is applicable for studies with an investigational medicinal product.> 
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study LVGHILQHGDVWKHODVWSDWLHQW¶V
last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and 
the competent authority within 15 days, including the reasons for the premature 
termination. 
 

 
 
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 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC and the Competent Authority.  
 
 
<In case the final study report will not be available within one year, another term should 
be defined including the reasons.> 
 
12.6 Public disclosure and publication policy 
The participants of this study have no conflicts of interest to disclose. 

 
 
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13. STRUCTURED RISK ANALYSIS  
NA 
 
13.1 Potential issues of concern 
 
< In this final paragraph of the research protocol a structured risk analysis which consists 
of a number of steps is required. The analysis should result in a comprehensive overall 
synthesis of the direct risks for the research subjects in this study in chapter 13.2. The risk 
considerations on the various issues listed below should be supported by up to date 
information and should be clearly described to allow a thorough review by the METC. For 
details one may refer to the previous chapters, the ,QYHVWLJDWRU¶V%URFKXUH,%RUDVLPLODU
document (if applicable), peer reviewed papers in (biomedical/scientific) journals. The 
issues below are provided to structure your considerations and allows an efficient 
communication with the METC when questions arise as a result of the review of your 
research protocol. The remarks per item are provided as a guidance for describing your 
considerations. Should issues not be applicable, please indicate so. 
For registered products to be used within the indication and not in combination with other 
products chapter 13.1 can be skipped; explain in chapter 13.2 why 13.1 is skipped > 
 
a. Level of knowledge about mechanism of action 
 
 
b. Previous exposure of human beings with the test product(s) and/or products with a 
similar biological mechanism 
 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material? 
 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
 
 
e. Analysis of potential effect 
 
 
f. Pharmacokinetic considerations 
 
 
g. Study population 
 
 
h. Interaction with other products 

 
 
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i. Predictability of effect 
 
 
j. Can effects be managed? 
 
 
13.2 Synthesis 
<should include uncertainties and the unknown and the overall risk:  
Make clear what measures have been taken to reduce what risks 
Make clear why in your opinion the remaining risks are acceptable for the subjects 
participating in the study> 
 
 
 
14. REFERENCES 
 
1. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of 
mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and 
recipients of a first cadaveric transplant. N Engl J Med. 1999 Dec 02;341(23):1725-30. 
2. https://www.usrds.org/reference.aspx UADRRTU. 
3. Kianda MN, Wissing KM, Broeders NE, Lemy A, Ghisdal L, Hoang AD, et al. Ineligibility for 
renal transplantation: prevalence, causes and survival in a consecutive cohort of 445 
patients. Clin Transplant. 2011 Jul-Aug;25(4):576-83. 
4. Goldsmith PJ, Fraser SM, Fitzpatrick M, Scott DJ, Ahmad N. Acute lower limb ischemia 
following pediatric renal transplantation. Pediatr Transplant. 2010 Nov;14(7):E93-5. 
5. Northcutt A, Zibari G, Tan TW, Coulter AH, Zhang WW. Does kidney transplantation to 
iliac artery deteriorate ischemia in the ipsilateral lower extremity with peripheral arterial 
disease? Vascular. 2015 Oct;23(5):490-3. 
6. Gouny P, Lenot B, Decaix B, Rondeau E, Kitzis M, Lacave R, et al. Aortoiliac surgery and 
kidney transplantation. Ann Vasc Surg. 1991 Jan;5(1):26-31. 
7. Piquet P, Berland Y, Coulange C, Olmer M, Mercier C, Rampal M. Aortoiliac 
reconstruction and renal transplantation: staged or simultaneous. Ann Vasc Surg. 1989 
Jul;3(3):251-6. 
8. Imanishi K, Hatakeyama S, Yamamoto H, Okamoto A, Imai A, Yoneyama T, et al. 
Posttransplant renal function and cardiovascular events are closely associated with the aortic 
calcification index in renal transplant recipients. Transplant Proc. 2014;46(2):484-8. 

 
 
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9. Adamec M, Janouoek L, Tooenovsky P, Lacha J. Renal transplantation combined with 
aortofemoral bypass using a fresh arterial allograft. Transpl Int. 2000;13 Suppl 1:S56-9. 
10. Ozcelik A, Treckmann J, Paul A, Witzke O, Sotiropoulos G, Nadalin S, et al. Results of 
kidney transplantation with simultaneous implantation of vascular graft. Transplant Proc. 
2007 Mar;39(2):509-10. 
11. Galazka Z, Grochowiecki T, Jakimowicz T, Kowalczewski M, Szmidt J. Is severe 
atherosclerosis in the aortoiliac region a contraindication for kidney transplantation? 
Transplant Proc. 2011 Oct;43(8):2908-10. 
12. Coosemans W, Nevelsteen A, Pirenne J, Vanrenterghem Y. Renal transplantation in 
patients with a vascular aortoiliac prosthesis. Transplant Proc. 1999 Jun;31(4):1925-7. 
13. Wright JG, Tesi RJ, Massop DW, Henry ML, Durham JR, Ferguson RM, et al. Safety of 
simultaneous aortic reconstruction and renal transplantation. Am J Surg. 1991 
Aug;162(2):126-30. 
14. Ahlmen J, Henriksson C, Claes G, Gelin LE, Thoren O. Successful kidney transplantation 
in a man with Dacron "trouser" prosthesis. Scand J Urol Nephrol. 1979;13(1):133-5. 
15. Gill R, Shapiro R, Kayler LK. Management of peripheral vascular disease compromising 
renal allograft placement and function: review of the literature with an illustrative case. Clin 
Transplant. 2011 May-Jun;25(3):337-44. 
16. Lacombe M. Aortoiliac surgery in renal transplant patients. J Vasc Surg. 1991 
May;13(5):712- 8. 
17. Sterioff S, Jr., Zachary JB, Williams GM. Dacron vascular grafts in renal transplant 
patients. Am J Surg. 1974 May;127(5):525-8. 
18. Turunc V, Eroglu A, Tabandeh B, Sarkislali K, Sener T, Aydin A, et al. Femoro-femoral 
Bypass for Graft Salvage in a Renal Transplant Patient With Aorto-iliac Occlusion: A Case 
Report. Transplant Proc. 2015 Jun;47(5):1511-4.