Urine CXCL10 Monitoring Trial in Kidney Transplant

• Sponsor: University of Manitoba (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03206801
• Collaborator: Canadian Institutes of Health Research (CIHR) (Other), Canadian National Transplant Research Program (Other)
• Enrollment: 420
• Locations: 7
• Arms: 2
• Anticipated Duration (Months): 67.9
• Patients Per Site: 60
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This is a Phase II-III multi-center prospective randomized controlled clinical trial of incident adult renal transplant patients.

The primary objective of this study is to determine if the early treatment of rejection, as detected by urinary CXCL10, will improve renal allograft outcomes.

Condition or Disease	Intervention/Treatment	Phase
Kidney Transplant; Complications; Rejection of Renal Transplant	Procedure: Kidney transplant biopsy	Phase 2/Phase 3

Detailed Description

This is a Phase II-III multi-center prospective randomized controlled clinical trial of incident adult renal transplant patients. Patients will be screened for eligibility (n≈485) and n≈420 will be enrolled and undergo post-transplant surveillance with urinary CXCL10. Two hundred and fifty patients deemed at high risk for rejection based on a confirmed elevated urine CXCL10 will undergo 1:1 randomization to the intervention and control arms, stratified by center. The total study duration is approximately 5 years; and there two main phases - screening and intervention.

All eligible, enrolled patients will undergo the Screening Phase (n≈420). Routine urine CXCL10 screening will be done from 2 weeks - 9 months post-transplant. We have previously shown that urine CXCL10 is elevated in ischemia-reperfusion injury, so screening will commence at 2 weeks (+/- 4 days) to exclude this as a potential confounding factor (60).

If patient develops a confirmed elevated urine CXCL10 level and is considered high risk for rejection, they will proceed to Randomization in the Intervention Phase, which can occur anytime between 2 weeks - 9 months post-transplant. Participants in the Intervention Arm will undergo renal biopsy to check for rejection. Biopsy-proven subclinical rejection will be treated per study protocol. Participants in the Control Arm will continue routine post-transplant surveillance with serum creatinine and proteinuria; serial urine samples will continue to be collected and analyzed (blinded), but not used to direct care. All randomized participants will undergo a 12-month study exit visit with protocol biopsy to determine primary, secondary and long-term outcomes.

Enrolled patients with persistently low urine CXCL10 and low risk of rejection from 2 weeks - 9 months post-transplant will be considered Off-Study (not randomized). They will undergo a 12-month study exit visit (+/- 7 days) to determine secondary and long-term outcomes.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 420 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is a Phase II-III multi-center prospective randomized controlled clinical trial of incident adult renal transplant patients. Patients with elevated urine CXCL10 will be randomized 1:1 to the intervention and control arms, stratified by center (~ 420 enrolled to urine CXCL10 screening for n=250 randomized participants).This is a Phase II-III multi-center prospective randomized controlled clinical trial of incident adult renal transplant patients. Patients with elevated urine CXCL10 will be randomized 1:1 to the intervention and control arms, stratified by center (~ 420 enrolled to urine CXCL10 screening for n=250 randomized participants).
• Masking: Single (Outcomes Assessor)
• Masking Description: The assessor of the primary outcome will be masked. As the intervention involves a study biopsy, based on an elevated urine CXCL10, it is not possible to blind the participant, care provider or investigator.
• Primary Purpose: Screening
• Official Title: A Randomized Controlled Trial of Urine CXCL10 Chemokine Monitoring Post-renal Transplant
• Actual Study Start Date: Apr 3, 2018
• Anticipated Primary Completion Date: Dec 1, 2022
• Anticipated Study Completion Date: Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intervention Participants with high urine CXCL10 randomized to the Intervention Arm will undergo a kidney transplant biopsy to check for rejection. Biopsy-proven subclinical rejection will be treated per study protocol.	Procedure: Kidney transplant biopsy; Elevated urine CXCL10 will trigger a study biopsy in patients randomized to the intervention arm. Subclinical rejection will be treated per protocol.; Other Names: Protocol biopsy
No Intervention: Control Participants with high urine CXCL10 randomized to the Control Arm will continue routine post-transplant surveillance with serum creatinine and proteinuria; serial urine samples will continue to be collected and analyzed (blinded), but not used to direct care.

Outcome Measures

Primary Outcome Measures

1. Death-censored graft loss [2 weeks-12 months post-transplant]

   Return to dialysis or re-transplant

2. Clinical indication biopsy-proven acute rejection [2 weeks-12 months post-transplant]

   Clinical rejection, Banff criteria

3. De novo donor specific antibody development [2 weeks-12 months post-transplant]

   De novo human leukocyte antibody (HLA) antibodies, donor specific

4. Subclinical tubulitis [12-month study exit biopsy]

   Subclinical rejection, Banff criteria

5. Interstitial fibrosis and inflammation (IFTA + i) [12-month study exit biopsy]

   IFTA + i, defined by Mayo criteria

Secondary Outcome Measures

1. Renal allograft function [6, 12, 24 and 60 months post-transplant]

   Change in eGFR (slope, ∆) and graft function (eGFR) (absolute, mL/min)

2. Microvascular inflammation [12-month study exit biopsy]

   Banff ptc, g, c4d, cg

3. Development IFTA from implantation to 12-months [12-month study exit biopsy]

   Banff ∆ ci, ct, cv

4. Days from transplantation to clinical-biopsy proven rejection [2 weeks-12 months post-transplant]

   Time to biopsy proven rejection

5. Albuminuria >300mg/day [6, 12, 24 and 60 months post-transplant]

   Urine albumin: Cr ratio

6. Cost-effectiveness of urine CXCL10 monitoring strategy [2 weeks-12 months post-transplant]

   Costs of urine CXCL10 screening

7. Quality of life [6 and 12 months post-transplant]

   EuroQOL (EQ-5DL)

8. Urine CXCL10 kinetics [2 weeks-12 months post-transplant]

   Change in urine CXCL10 levels in response to rejection therapy

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Participants must be able to understand and provide written informed consent

2. Stated willingness to comply with all study procedures and availability for the duration of the study

3. All ethnic and gender groups will have equal access to the study

4. Incident adult (age ≥18) renal transplant patients with a living or deceased donor kidney transplant

5. Confirmed elevated urine CXCL10:Cr without a urinary tract infection or menses.

Exclusion Criteria:

1. Primary non-function

2. Blood group (ABO) incompatible

3. Pre-transplant donor specific antibody (DSA) positive

4. Human leukocyte (HLA) 0 HLA antigen D-related (DR) and 0 major HLA class 2 (DQ) mis-match

5. Presence of other transplanted organ or co-transplanted organ

6. Active infection at the time of randomization

7. Followed outside of investigational center

8. Participation in other interventional trials within 4-weeks post-transplant or anytime post-transplant till study end at 12-months

9. Intention to not use a maintenance immunosuppression regimen consisting of calcineurin inhibitor (CNI) and anti-proliferative agents

10. Any condition that, in the opinion of the investigator, would pose risk to the subject's safe participation, or interfere with their ability to comply with the study requirements, or may impact the quality of interpretation of the data.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
2	University of Manitoba, Transplant Manitoba Adult Kidney Program	Winnipeg	Manitoba	Canada	R3A 1R9
3	Western University	London	Ontario	Canada
4	University of Ottawa	Ottawa	Ontario	Canada
5	McGill	Montreal	Quebec	Canada
6	Centre de recherche du CHUM (CRCHUM)	Montréal	Quebec	Canada
7	Université Laval	Québec City	Quebec	Canada

Sponsors and Collaborators

• University of Manitoba
• Canadian Institutes of Health Research (CIHR)
• Canadian National Transplant Research Program

Investigators

• Principal Investigator: Julie Ho, MD, University of Manitoba

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Manitoba
• ClinicalTrials.gov Identifier: NCT03206801
• Other Study ID Numbers: B2017:076; 364003; TMCT-04
• First Posted: Jul 2, 2017
• Last Update Posted: May 25, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Manitoba: Urine biomarker; CXCL10 chemokine; Post-transplant monitoring; Protocol biopsy

Study Results

No Results Posted as of May 25, 2022