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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
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
Secondary ID [1] 301847 0
None
Universal Trial Number (UTN)
Trial acronym
INCEPTION
Linked study record

Health condition
Health condition(s) or problem(s) studied:
End stage kidney disease/Kidney failure 317952 0
Kidney Transplantation 318334 0
Kidney transplant outcome 318335 0
Condition category
Condition code
Renal and Urogenital 315985 315985 0 0
Kidney disease
Inflammatory and Immune System 315987 315987 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
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.
Intervention code [1] 317874 0
Diagnosis / Prognosis
Intervention code [2] 318142 0
Early Detection / Screening
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).
Control group
Historical

Outcomes
Primary outcome [1] 324189 0
De novo donor-specific anti-HLA antibody post-transplantation detected using Luminex bead technology. Data will be extracted from healthcare records and registries.
Timepoint [1] 324189 0
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.
Primary outcome [2] 324191 0
Acute rejection - biopsy-proven. Data will be extracted from healthcare records and registries.
Timepoint [2] 324191 0
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.
Primary outcome [3] 324512 0
Allograft loss (date and cause), defined as returned to dialysis or death. Routinely captured as follow-up data from registries and healthcare records.
Timepoint [3] 324512 0
Data will be collected for this outcome from date of transplantation until 31st December 2020.
Secondary outcome [1] 383970 0
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.
Timepoint [1] 383970 0
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.
Secondary outcome [2] 383975 0
Kidney allograft function (serum creatinine and creatinine-derived calculated estimated glomerular filtration rate) will be extracted from local healthcare records.
Timepoint [2] 383975 0
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.
Secondary outcome [3] 383977 0
Death (date and cause) will be extracted from registries and local healthcare records.
Timepoint [3] 383977 0
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.
Secondary outcome [4] 385779 0
Urine proteinuria (urine protein/creatinine ratio) will be extracted from local healthcare records
Timepoint [4] 385779 0
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.

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.
Minimum age
2 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Both
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.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/11/2020
Actual
Date of last participant enrolment
Anticipated
31/07/2021
Actual
Date of last data collection
Anticipated
31/12/2021
Actual
Sample size
Target
550
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 16939 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 16940 0
Westmead Hospital - Westmead
Recruitment hospital [3] 16943 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 16944 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [5] 17140 0
Perth Children's Hospital - Nedlands
Recruitment hospital [6] 17141 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 30597 0
6009 - Nedlands
Recruitment postcode(s) [2] 30598 0
2145 - Westmead
Recruitment postcode(s) [3] 30819 0
4101 - South Brisbane
Recruitment postcode(s) [4] 30820 0
3052 - Parkville
Recruitment outside Australia
Country [1] 22685 0
New Zealand
State/province [1] 22685 0
Auckland
Country [2] 22781 0
United Kingdom
State/province [2] 22781 0
Cambridge
Country [3] 22782 0
Belgium
State/province [3] 22782 0
Brussels
Country [4] 22783 0
Netherlands
State/province [4] 22783 0
Rotterdam

Funding & Sponsors
Funding source category [1] 306004 0
Government body
Name [1] 306004 0
National Health and Medical Research Council
Country [1] 306004 0
Australia
Funding source category [2] 306009 0
Charities/Societies/Foundations
Name [2] 306009 0
Department of Health in Western Australia
Country [2] 306009 0
Australia
Funding source category [3] 306477 0
University
Name [3] 306477 0
Raine Medical Research Foundation at the University of Western Australia
Country [3] 306477 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
35 Stirling Hwy, Crawley, 6009, Western Australia
Country
Australia
Secondary sponsor category [1] 306472 0
None
Name [1] 306472 0
None
Address [1] 306472 0
None
Country [1] 306472 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306240 0
Sir Charles Gairdner Osborne Park Health Care Group
Ethics committee address [1] 306240 0
Ethics committee country [1] 306240 0
Australia
Date submitted for ethics approval [1] 306240 0
Approval date [1] 306240 0
20/12/2018
Ethics approval number [1] 306240 0
RGS 930

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103214 0
Prof Wai Lim
Address 103214 0
Department of Renal Medicine
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands, Western Australia, 6009
Country 103214 0
Australia
Phone 103214 0
+618 93462799
Fax 103214 0
+618 93463942
Email 103214 0
wai.lim@health.wa.gov.au
Contact person for public queries
Name 103215 0
Wai Lim
Address 103215 0
Department of Renal Medicine
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands, Western Australia, 6009
Country 103215 0
Australia
Phone 103215 0
+618 93462799
Fax 103215 0
+618 93463942
Email 103215 0
wai.lim@health.wa.gov.au
Contact person for scientific queries
Name 103216 0
Wai Lim
Address 103216 0
Department of Renal Medicine
Sir Charles Gairdner Hospital
Hospital Avenue
Nedlands, Western Australia, 6009
Country 103216 0
Australia
Phone 103216 0
+618 93462799
Fax 103216 0
+618 93463942
Email 103216 0
wai.lim@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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


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
SourceTitleYear of PublicationDOI
EmbaseImprove 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.2021https://dx.doi.org/10.1186/s12882-021-02619-0
N.B. These documents automatically identified may not have been verified by the study sponsor.