UMIN-CTR Clinical Trial

Public title

Innovating Post-transplant Care: Employing Donor-Derived Cell-Free DNA measured by SNP for Early Graft Dysfunction Detection"

Acronym

Japanese SNP and Donor-Derived cfDNA in Organ Transplantation = J-SPOT Study

Scientific Title

Establishment of a Diagnostic Method for Graft Dysfunction after Organ Transplantation Using Donor-Derived Cell-Free DNA Measurement (Liquid Biopsy) Utilizing Japanese SNP

Scientific Title:Acronym

Japanese SNP and Donor-Derived cfDNA in Organ Transplantation = J-SPOT Study

Region

Japan

Condition

Heart transplant, Lung Transplant, Liver transplant, Kidney Transplant, Pancreas Transplant

Classification by specialty

Gastrointestinal surgery	Hepato-biliary-pancreatic surgery	Vascular surgery
Chest surgery	Urology

Classification by malignancy

Others

Genomic information

YES

Narrative objectives1

The primary objective of this research is to calculate donor-derived cfDNA using a next-generation sequencing-based capture method that utilizes a Japanese-specific SNP polymorphism panel in six major organ transplantations (heart, lung, liver, pancreas, kidney, and small intestine). The aim is to validate the utility of a domestically unique transplant organ dysfunction diagnostic method in Japan.

The main objective of this research is to analyze the changes in early post-transplant donor-derived cfDNA for each major organ transplantation, assess the correlation between histologically diagnosed rejection severity and donor-derived cfDNA, and evaluate the correlation between protocol biopsy results and donor-derived cfDNA as a liquid biopsy test. Specifically, the primary goal is to establish organ-specific threshold values and calculate the Diagnostic Test Accuracy (sensitivity, specificity, ROC area under the curve (AUC), positive predictive value, negative predictive value) for organ dysfunction, including rejection reactions, for each organ.

A crucial aspect of this study is obtaining data specific to the Japanese population. By conducting a collaborative, multi-center study involving multiple organ types, the aim is to establish diagnostic technology as a liquid biopsy on a national scale. The analysis of collected clinical information and built databases will facilitate the creation of new risk prediction and objective criteria for post-transplant management, leading to the establishment of post-transplant management protocols based on these findings.

Basic objectives2

Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Pragmatic

Developmental phase

Not applicable

Primary outcomes

This research involves the following key analyses in the context of six organ transplantations:

1.Analysis of acute-phase changes in donor-derived cell-free DNA (cfDNA) in the acute period, with a focus on detecting ischemia-reperfusion injury and recording changes until the stable phase. Record baseline values after acute-phase changes.
2.Analysis of factors influencing baseline values, including age, HLA mismatch count, gender, surgery duration, ischemia time, type of immunosuppressive drugs, physical differences, organ-specific assessment criteria, CMV status, and initial immunosuppressive agents.
3.Survival analysis for one year post-transplantation based on grouping the donor-derived cfDNA values obtained using the baseline value (value one month post-transplant).
4.Correlation analysis between measured donor-derived cfDNA and the degree of rejection reaction in the transplanted organs.
5.Correlation analysis between measured donor-derived cfDNA and organ function assessment criteria or existing markers.
6.Analysis of donor-derived cfDNA values corresponding to the timing of tissue sample collection based on histological diagnostic criteria in each major organ transplantation, comparing these values between i) rejection reaction groups (ACR/AMR/CR), ii) non-rejection reaction groups (organ dysfunctions other than rejection reactions), and iii) groups without histological abnormalities.
7.ROC curve analysis: Conduct ROC analysis between the above-mentioned groups to determine sensitivity, specificity, positive predictive value, and negative predictive value.
8.Perform multivariate analysis by combining donor-derived cfDNA, patient profiles, organ-specific information for transplanted organs, post-transplant treatment methods, and other factors to assess whether donor-derived cfDNA is an independent predictor of transplantation outcomes.

Key secondary outcomes

For the purpose of diagnosing organ dysfunctions, including rejection reactions, samples collected at the time of diagnosis and post-diagnosis are analyzed to track the changes in donor-derived cfDNA due to treatment interventions.

Grouping based on baseline donor-derived cfDNA values (e.g., using a cutoff value of 0.5%) and illustrating the occurrence of de novo Donor Specific Antibodies (dnDSA) using a Kaplan-Meier plot. The horizontal axis represents the number of days after the initial test, while the vertical axis represents the rate of dnDSA occurrence.
Analyzing the risk of donor-derived cfDNA and dnDSA occurrence using a Cox proportional hazards model and determining hazard ratios. The cutoff value will be determined for each organ.

This analysis aims to understand how changes in donor-derived cfDNA relate to the development of dnDSA in the context of organ dysfunctions, allowing for the determination of risk and potential interventions based on baseline values.

Study type

Observational

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

18

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

This information outlines the eligibility criteria for the study:

Target Diseases:
The study includes individuals who are either newly receiving organ transplants (heart, lung, liver, pancreas, kidney, or small intestine) or have already received organ transplants.
Patient Background Information (e.g., Age and Gender):
Patients who provided consent are 18 years or older at the time of consent.
For liver transplant patients, consent can be obtained when the patient is under 3 years of age.
The age at the time of transplantation is not specifically mentioned, as long as it fulfills the conditions mentioned above.
Consent Obtained in Writing:
The consent for participation in the study is obtained in written form.
Additional Notes:

Specific details regarding disease classification (duration of illness, disease stage, disease type, severity, etc.), hospitalization or outpatient status, previous treatments, and recurrence are not specified.
The study primarily focuses on single-organ transplant patients. However, exceptions are made for pancreas-kidney simultaneous transplant patients and liver-small intestine simultaneous transplant patients, as there are limited cases of pancreas and small intestine transplants.
Pancreas-kidney simultaneous transplant patients are registered as pancreas transplant patients, and liver-small intestine simultaneous transplant patients are registered as small intestine transplant patients.
No specific clinical, geographical, or temporal criteria are mentioned as eligibility criteria for the study.

Key exclusion criteria

The provided information outlines certain exclusion criteria for the study:

1. Pregnancy:
Pregnant individuals are excluded from participation.
2. Twin-to-Twin Transplants:
Cases involving twin-to-twin transplants are not eligible.
3. History of Bone Marrow Transplant:
Individuals with a history of bone marrow transplant are not included.
4. Multiple Organ Transplants:
The study primarily focuses on single-organ transplant patients. However, exceptions are made for pancreas-kidney simultaneous transplant patients and liver-small intestine simultaneous transplant patients.
5. Re-transplantation:
Patients who have undergone re-transplantation are excluded from the study.

Note regarding Multiple Organ Transplants:
The study allows for exceptions in cases of pancreas-kidney simultaneous transplant patients and liver-small intestine simultaneous transplant patients. These patients may be eligible for registration.

Target sample size

420

Name of lead principal investigator

1st name	Yuko
Middle name
Last name	Kitagawa

Organization

Keio University School of Medicine

Division name

Department of Surgery

Zip code

160-8582

Address

35 Shinanomachi Shinjuku, Tokyo

TEL

03-5363-3801

Email

kitagawa@a3.keio.jp

Name of contact person

1st name	Yohei
Middle name
Last name	Yamada

Organization

Keio University School of Medicine

Division name

Department of Pediatric Surgery

Zip code

160-8582

Address

35 Shinanomachi Shinjuku, Tokyo

TEL

03-5363-3024

Homepage URL

Email

yohei.z7@keio.jp

Institute

Keio University School of Medicine

Institute

Department

Personal name

Organization

Japan Agency for Medical Research and Development

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Keio University School of Medicine Ethics Committee

Address

35 Shinanomachi, Shinjuku, Tokyo

Tel

03-5363-3503

Email

med-rinri-jimu@adst.keio.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2023

Year

10

Month

31

Day

URL releasing protocol

Publication of results

Unpublished

URL related to results and publications

Number of participants that the trial has enrolled

Results

Results date posted

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Participant flow

Adverse events

Outcome measures

Plan to share IPD

IPD sharing Plan description

Recruitment status

Enrolling by invitation

Date of protocol fixation

2023

Year

09

Month

05

Day

Date of IRB

2023

Year

09

Month

05

Day

Anticipated trial start date

2023

Year

12

Month

01

Day

Last follow-up date

2030

Year

07

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

This research involves several cohorts and sample collection procedures:

1, New Transplant Cohort (Longitudinal Cohort):
For new transplant cases, a longitudinal cohort is planned.
Each patient in new transplant cases provides 12 samples according to the protocol.
If protocol biopsies are conducted during the observation period or if organ dysfunction events occur, samples are collected according to the predefined criteria for protocol biopsy samples and organ dysfunction event samples. These samples are registered in the REDcap database as protocol biopsy and organ dysfunction events.
Protocol samples and event samples can be analyzed as part of the cross-cohort during data analysis.

2, Cross-sectional Cohort (Patients with Organ Dysfunction):
This cohort includes patients who have already undergone transplantation and are suspected of having organ dysfunction, undergoing histological biopsies, or receiving treatment interventions.
Samples are obtained at the time of histological diagnosis, particularly when acute rejection reactions are diagnosed, and the diagnostic utility of acute rejection reactions is analyzed.
Samples are also collected at the time of organ dysfunction events other than acute rejection reactions.
Comparisons are made between the donor-derived cfDNA of the acute rejection reaction group and the organ dysfunction group without rejection reactions.

3, Cross-sectional Cohort (Patients Undergoing Protocol Biopsies):
This cohort comprises patients who have already undergone transplantation and are undergoing protocol biopsies.
Samples are obtained at the time when no organ dysfunction, including histological acute rejection reactions, is observed.
It's important to note that protocol biopsies are performed for clinical screening purposes related to organ dysfunction and are not performed for research purposes.

Registered date

2023

Year

10

Month

31

Day

Last modified on

2023

Year

10

Month

31

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000058690