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Trial registered on ANZCTR
Registration number
ACTRN12620000911998
Ethics application status
Approved
Date submitted
19/06/2020
Date registered
14/09/2020
Date last updated
14/09/2020
Date data sharing statement initially provided
14/09/2020
Type of registration
Prospectively registered
Titles & IDs
Public title
Gene Compatibility and Outcomes of Paediatric and Adolescent Patients of Parental Donor Kidney Transplants
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Scientific title
Effect of In-Depth Immunological Risk Assessment on Genetic-Compatibility and Clinical Outcomes in Paediatric and Adolescent Patients of Parental Donor Kidney Transplants: The INCEPTION Study
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Secondary ID [1]
301847
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None
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Universal Trial Number (UTN)
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Trial acronym
INCEPTION
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
End stage kidney disease/Kidney failure
317952
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Kidney Transplantation
318334
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Kidney transplant outcome
318335
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Condition category
Condition code
Renal and Urogenital
315985
315985
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0
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Kidney disease
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Inflammatory and Immune System
315987
315987
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0
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Other inflammatory or immune system disorders
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Intervention/exposure
Study type
Observational
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Patient registry
False
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Target follow-up duration
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Target follow-up type
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Description of intervention(s) / exposure
1) In Australia and New Zealand, each donor-recipient pair will be consented for a single blood sample with DNA isolated for high-resolution molecular human leukocyte antigen (HLA)-typing across HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DPA1, -DPB1, -DQA1, and -DQB1 (if required). In other countries, the sera/DNA are already stored for all donor-recipient pairs that fulfil the inclusion criteria (will need updated waiver of consent) and testing for high-resolution molecular HLA typing will be undertaken if required. The high resolution HLA typing will be used to identify and calculate the number of eplet mismatches (using HLAMatchmaker and other computational algorithm), immunogenic/non-immunogenic eplet mismatches, PIRCHE score, amino acid and electrostatic mismatches. Broad antigen low- to intermediate resolution HLA typing would have already been undertaken at time of transplant as part of standard kidney allocation/ transplantation.
2) Participants (recipients and corresponding donors transplanted between January 1990 and December 2020) will be identified from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry and country-specific registries/health care records.
3) Patient and donor characteristics of donor and recipient age, donor and recipient sex, time on dialysis prior to transplant, comorbidities (diabetes, coronary artery disease, peripheral vascular disease, cerebrovascular disease), smoking history and types/level of immunosuppressive medications. Outcome measures include rejection, allograft loss, pre-transplant and de novo donor-specific anti-HLA-antibody, kidney allograft biopsy data, hospitalisations and death. These data will be extracted from registry and local healthcare records.
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Intervention code [1]
317874
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Diagnosis / Prognosis
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Intervention code [2]
318142
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Early Detection / Screening
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Comparator / control treatment
Comparison between paediatric and adolescent kidney transplant recipients aged <=18 years of maternal vs. paternal donor kidneys in Australia, New Zealand, United Kingdom, Netherlands and Belgium between January 1990 and December 2020 (inclusive).
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Control group
Historical
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Outcomes
Primary outcome [1]
324189
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De novo donor-specific anti-HLA antibody post-transplantation detected using Luminex bead technology. Data will be extracted from healthcare records and registries.
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Assessment method [1]
324189
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Timepoint [1]
324189
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These antibodies are tested routinely in all kidney transplant recipients post-transplant as part of routine monitoring (typically annually of the anniversary of transplant) or for clinical indication (at time of investigation for possible kidney allograft rejection). No additional testing will be undertaken for the purpose of this study. Data will be collected annually after kidney transplantation until the end of follow-up time of 31st Dec 2020.
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Primary outcome [2]
324191
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Acute rejection - biopsy-proven. Data will be extracted from healthcare records and registries.
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Assessment method [2]
324191
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Timepoint [2]
324191
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Biopsy-proven acute rejection episode(s) and type/severity and treatment(s) will be performed/captured when clinically indicated as per routine post-transplant clinical practice. No additional testing will be undertaken for the purpose of this study (with follow-up until 31st December 2020). Data will be collected annually after kidney transplantation until the end of follow-up time of 31st Dec 2020.
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Primary outcome [3]
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Allograft loss (date and cause), defined as returned to dialysis or death. Routinely captured as follow-up data from registries and healthcare records.
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Assessment method [3]
324512
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Timepoint [3]
324512
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Data will be collected for this outcome from date of transplantation until 31st December 2020.
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Secondary outcome [1]
383970
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CADI score (kidney allograft biopsy), which quantifies the amount of chronic damage to the allograft, with the score calculated from a total of six parameters of: (a) diffuse or focal inflammation and (b) fibrosis in the interstitium, (c) mesangial matrix increase and (d) sclerosis in glomeruli, (e) intimal proliferation of vessels, and (f) tubular atrophy; with each individual parameter being scored between 0 and 3 as described in other studies. The severity of transplant glomerulopathy (part of the CADI score) will also be collected from routine/protocol or clinical indicated biopsy data of each recipient. These data will be extracted from healthcare records through review of pathology databases or medical case notes.
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Assessment method [1]
383970
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Timepoint [1]
383970
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All allograft biopsies undertaken post-transplant (for protocol or clinical indication reasons) will be extracted and CADI score and severity of transplant glomerulopathy reported by independent pathologist. Data will be collected annually after kidney transplantation until the end of follow-up time of 31st Dec 2020.
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Secondary outcome [2]
383975
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Kidney allograft function (serum creatinine and creatinine-derived calculated estimated glomerular filtration rate) will be extracted from local healthcare records.
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Assessment method [2]
383975
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Timepoint [2]
383975
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Data will be collected at 3, 6, 12 months and then annually after transplantation until the end of follow-up time of 31st Dec 2020 or at time of allograft loss/death.
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Secondary outcome [3]
383977
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Death (date and cause) will be extracted from registries and local healthcare records.
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Assessment method [3]
383977
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Timepoint [3]
383977
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Data will be collected annually after transplantation until the end of follow-up time of 31st Dec 2020 or at time of allograft loss/death.
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Secondary outcome [4]
385779
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Urine proteinuria (urine protein/creatinine ratio) will be extracted from local healthcare records
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Assessment method [4]
385779
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Timepoint [4]
385779
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Data will be collected at 3, 6, 12 months and then annually after transplantation until the end of follow-up time of 31st Dec 2020 or at time of allograft loss/death.
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Eligibility
Key inclusion criteria
Paediatric and adolescent patients with ESKD who have received a parental donor
kidney transplant aged less than or equal to 18 years between January 1990 and December 2020 will be recruited. Corresponding parental donors will also be recruited.
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Minimum age
2
Years
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Maximum age
18
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
1) Kidney transplant recipients aged over 18 years of age at time of transplantation.
2) Kidney transplant recipients of deceased donor kidneys.
3) Recipients (and corresponding donors) who are not contactable or alive (at time of recruitment) in Australia and New Zealand will be excluded. Please note that for other countries of United Kingdom, Belgium and Netherlands where a waiver of consent to extract data/utilise stored sera and DNA are permissible, the inclusion of recipient/donor pairs whom are not contactable or are deceased may be included.
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Study design
Purpose
Natural history
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Duration
Longitudinal
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Selection
Defined population
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Timing
Both
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Statistical methods / analysis
The total number of broad antigen HLA, eplet and other mismatches (i.e. HLA-mismatches at HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DPA1, -DPB1, -DQA1, and -DQB1 alleles, with the high resolution HLA typing use to identify and calculate the number of eplet mismatches using HLAMatchmaker or other computational algorithm). The linearity of the relationship between the number of HLA and eplet mismatches and each primary outcome will be determined using restricted cubic spline modelling, The association between broad antigen and eplet HLA mismatches will be examined using Pearson correlations. A Pearson’s correlation coefficient of 0.1 to 0.3 is considered weak, 0.4 to 0.6 moderate and 0.7 to 0.9 strong correlations. Correlations will be presented with 95% confidence intervals (95% CI) and corresponding p-values.
The associations between the total number of broad antigen HLA mismatches and the primary and secondary outcomes will be determined using Cox regression (for time to event analyses including the development of de novo donor-specific anti-HLA antibody, acute rejection, allograft loss, death and CADI/transplant glomerulopathy) and linear mixed modelling/linear regression analyses (for repeated measures and continuous variable outcomes such as graft function and urine proteinuria) as appropriate (Model 1). Three other models including total number of eplet mismatches (Model 2), number of immunogenic and non-immunogenic eplet mismatches (Model 3) or amino acid mismatches, electrostatic mismatches and PIRCHE score (Model 4) will be created. We will compare the test performances of Models 2, 3 and 4 vs. Model 1 for the various outcomes. Covariates that will be included in the adjusted model (including donor and recipient sex, prevalent and de novo comorbid conditions [including diabetes, coronary artery disease, sensitisation status, pre-transplant anti-HLA antibody, peripheral vascular disease, cerebrovascular disease], smoking history and types/level of immunosuppressive medications) will include the covariates with p-values of <0.1 in the unadjusted models using the Lasso selection method, although donor and recipient age, transplant era, race and dialysis duration will be included in all models because of their biological relationship with clinical outcomes. Results will be expressed as unadjusted and adjusted hazards ratios (HR) or beta-coefficients with 95% CI.
Receiver operating characteristics under the curve (ROC AUC) and net reclassification index will be used to determine whether eplet and other mismatches improves the discrimination of outcomes compared to standard broad antigen HLA mismatches. Discrimination refers to the ability of the model to distinguish individuals with and without the outcomes of interest whereby an AUC of 1 implies perfect discrimination and an AUC of 0.5 represents random discrimination. The Sidak option provides adjusted p-values comparing the ROC areas between the 2 models, assuming a “gold standard” being broad antigen HLA mismatches. For the ROC analysis, the primary comparison measure between the models (with and without the exposure) will be the point estimate integrated Area under the ROC (iAUC), and each iAUC for each model constructed using a bootstrap procedure as appropriate for time-dependent ROC curve. In addition, using AUC as the measure of predictive performance, a series of Cox regression models where each model containing a dichotomised indicator of the eplet mismatch threshold(s) will also be determined.
For sensitivity analysis (of biological relevance), separate statistical models (as above) will be constructed for class I (i.e. HLA-A, -B and -C eplet mismatches) and II (i.e. HLA-DP, DQ and-DR eplet mismatches) alleles given the dissimilar expression, distribution and function between the two classes of HLA alleles.
Statistical evaluation will be performed by SPSS V10 software program, SAS software 9.4 and STATA version 11. P-values of less than 0.05 will be considered statistically significant.
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
2/11/2020
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Actual
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Date of last participant enrolment
Anticipated
31/07/2021
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Actual
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Date of last data collection
Anticipated
31/12/2021
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Actual
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Sample size
Target
550
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
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Recruitment hospital [1]
16939
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Sir Charles Gairdner Hospital - Nedlands
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Recruitment hospital [2]
16940
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Westmead Hospital - Westmead
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Recruitment hospital [3]
16943
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The Children's Hospital at Westmead - Westmead
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Recruitment hospital [4]
16944
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The Royal Childrens Hospital - Parkville
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Recruitment hospital [5]
17140
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Perth Children's Hospital - Nedlands
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Recruitment hospital [6]
17141
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Queensland Children's Hospital - South Brisbane
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Recruitment postcode(s) [1]
30597
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6009 - Nedlands
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Recruitment postcode(s) [2]
30598
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2145 - Westmead
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Recruitment postcode(s) [3]
30819
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4101 - South Brisbane
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Recruitment postcode(s) [4]
30820
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3052 - Parkville
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Recruitment outside Australia
Country [1]
22685
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New Zealand
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State/province [1]
22685
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Auckland
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Country [2]
22781
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United Kingdom
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State/province [2]
22781
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Cambridge
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Country [3]
22782
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Belgium
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State/province [3]
22782
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Brussels
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Country [4]
22783
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Netherlands
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State/province [4]
22783
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Rotterdam
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Funding & Sponsors
Funding source category [1]
306004
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Government body
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Name [1]
306004
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National Health and Medical Research Council
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Address [1]
306004
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GPO Box 1421
Canberra ACT 2601
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Country [1]
306004
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Australia
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Funding source category [2]
306009
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Charities/Societies/Foundations
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Name [2]
306009
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Department of Health in Western Australia
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Address [2]
306009
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Please note funding is co-shared between the organisations of Department of Health in Western Australia and Raine Medical Research Foundation at the University of Western Australia.
Address: Department of Health - 189 Royal St, East Perth WA 6004 (Department of Health).
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Country [2]
306009
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Australia
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Funding source category [3]
306477
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University
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Name [3]
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Raine Medical Research Foundation at the University of Western Australia
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Address [3]
306477
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Please note funding is co-shared between the organisations of Department of Health in Western Australia and Raine Medical Research Foundation at the University of Western Australia.
Address: Raine Medical Research Foundation - Suite 24, Hollywood Specialist Centre, 95 Monash Ave, Nedlands WA 6009.
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Country [3]
306477
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Australia
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Primary sponsor type
University
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Name
University of Western Australia
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Address
35 Stirling Hwy, Crawley, 6009, Western Australia
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Country
Australia
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Secondary sponsor category [1]
306472
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None
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Name [1]
306472
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None
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Address [1]
306472
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None
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Country [1]
306472
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
306240
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Sir Charles Gairdner Osborne Park Health Care Group
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Ethics committee address [1]
306240
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Level 2, Hospital Ave, Nedlands, Western Australia, 6009
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Ethics committee country [1]
306240
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Australia
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Date submitted for ethics approval [1]
306240
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Approval date [1]
306240
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20/12/2018
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Ethics approval number [1]
306240
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RGS 930
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Summary
Brief summary
Kidney transplantation is the treatment of choice for patients with end-stage kidney disease (ESKD) because if confers a significant survival benefit compared to dialysis treatment. For the large majority of paediatric and adolescent patients with ESKD, parents are the preferred source of donor kidneys for transplantation. Recent study has suggested that kidneys from mothers are more likely to reject compared to kidneys from fathers, but the reasons for this observation is unknown. This study aims to examine in-depth the potential difference in genetic (i.e. immunological) compatibility between donors and patients) using novel molecular techniques, which may help to better stratify the risk of adverse allograft outcomes after kidney transplantation from mothers and fathers. With these findings, this will enable clinicians and patients/families to make a better-informed decision regarding the selection of the most appropriate parental donor kidneys for transplantation.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
103214
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Prof Wai Lim
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Address
103214
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Department of Renal Medicine
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands, Western Australia, 6009
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Country
103214
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Australia
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Phone
103214
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+618 93462799
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Fax
103214
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+618 93463942
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Email
103214
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[email protected]
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Contact person for public queries
Name
103215
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Prof Wai Lim
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Address
103215
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Department of Renal Medicine
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands, Western Australia, 6009
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Country
103215
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Australia
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Phone
103215
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+618 93462799
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Fax
103215
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+618 93463942
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Email
103215
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[email protected]
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Contact person for scientific queries
Name
103216
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Prof Wai Lim
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Address
103216
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Department of Renal Medicine
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands, Western Australia, 6009
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Country
103216
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Australia
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Phone
103216
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+618 93462799
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Fax
103216
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+618 93463942
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Email
103216
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Not considered in ethics application but may be considered once project has been completed with agreements from all investigators
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
Source
Title
Year of Publication
DOI
Embase
Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.
2021
https://dx.doi.org/10.1186/s12882-021-02619-0
N.B. These documents automatically identified may not have been verified by the study sponsor.
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