Urine CXCL10 Monitoring Trial in Kidney Transplant

Kidney Transplant; Complications Clinical Trial

Official title:

A Randomized Controlled Trial of Urine CXCL10 Chemokine Monitoring Post-renal Transplant

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03206801
• Other study ID #: B2017:076
• Secondary ID: 364003TMCT-04
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: April 3, 2018
• Est. completion date: December 31, 2025

Study information

• Verified date: December 2023
• Source: University of Manitoba
• Contact: Kiran Sran, MSc
• Phone: 204-787-3618
• Email: ksran2[@]exchange.hsc.mb.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 420
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 gross hematuria.

Exclusion Criteria:

1. Primary non-function

2. Blood group (ABO) incompatible

3. Pre-transplant donor specific antibody (DSA) positive (MFI>1000 OR positive flow crossmatch)

4. Human leukocyte (HLA) 0 HLA antigen D-related (DR) + 0 major HLA class 2 (DQ) mismatch

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

6. Medical contraindication to biopsy or rejection treatment

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.

Related Conditions & MeSH terms

• Kidney Transplant; Complications
• Rejection of Renal Transplant

Intervention

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.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Canada	University of Calgary	Calgary	Alberta
Canada	Western University	London	Ontario
Canada	McGill	Montreal	Quebec
Canada	Centre de recherche du CHUM (CRCHUM)	Montréal	Quebec
Canada	University of Ottawa	Ottawa	Ontario
Canada	Université Laval	Québec City	Quebec
Canada	University of Manitoba, Transplant Manitoba Adult Kidney Program	Winnipeg	Manitoba

Sponsors (3)

Lead Sponsor	Collaborator
University of Manitoba	Canadian Institutes of Health Research (CIHR), Canadian National Transplant Research Program

Countries where clinical trial is conducted

Australia,  Canada, 

References & Publications (9)

Blydt-Hansen TD, Gibson IW, Gao A, Dufault B, Ho J. Elevated urinary CXCL10-to-creatinine ratio is associated with subclinical and clinical rejection in pediatric renal transplantation. Transplantation. 2015 Apr;99(4):797-804. doi: 10.1097/TP.000000000000 — View Citation

Hirt-Minkowski P, Amico P, Ho J, Gao A, Bestland J, Hopfer H, Steiger J, Dickenmann M, Burkhalter F, Rush D, Nickerson P, Schaub S. Detection of clinical and subclinical tubulo-interstitial inflammation by the urinary CXCL10 chemokine in a real-life setti — View Citation

Hirt-Minkowski P, Ho J, Gao A, Amico P, Koller MT, Hopfer H, Rush DN, Nickerson PW, Schaub S. Prediction of Long-term Renal Allograft Outcome By Early Urinary CXCL10 Chemokine Levels. Transplant Direct. 2015 Sep 24;1(8):e31. doi: 10.1097/TXD.0000000000000 — View Citation

Hirt-Minkowski P, Rush DN, Gao A, Hopfer H, Wiebe C, Nickerson PW, Schaub S, Ho J. Six-Month Urinary CCL2 and CXCL10 Levels Predict Long-term Renal Allograft Outcome. Transplantation. 2016 Sep;100(9):1988-96. doi: 10.1097/TP.0000000000001304. — View Citation

Ho J, Rush DN, Karpinski M, Storsley L, Gibson IW, Bestland J, Gao A, Stefura W, HayGlass KT, Nickerson PW. Validation of urinary CXCL10 as a marker of borderline, subclinical, and clinical tubulitis. Transplantation. 2011 Oct 27;92(8):878-82. doi: 10.109 — View Citation

Ho J, Rush DN, Krokhin O, Antonovici M, Gao A, Bestland J, Wiebe C, Hiebert B, Rigatto C, Gibson IW, Wilkins JA, Nickerson PW. Elevated Urinary Matrix Metalloproteinase-7 Detects Underlying Renal Allograft Inflammation and Injury. Transplantation. 2016 Ma — View Citation

Ho J, Sharma A, Mandal R, Wishart DS, Wiebe C, Storsley L, Karpinski M, Gibson IW, Nickerson PW, Rush DN. Detecting Renal Allograft Inflammation Using Quantitative Urine Metabolomics and CXCL10. Transplant Direct. 2016 May 19;2(6):e78. doi: 10.1097/TXD.00 — View Citation

Hricik DE, Nickerson P, Formica RN, Poggio ED, Rush D, Newell KA, Goebel J, Gibson IW, Fairchild RL, Riggs M, Spain K, Ikle D, Bridges ND, Heeger PS; CTOT-01 consortium. Multicenter validation of urinary CXCL9 as a risk-stratifying biomarker for kidney tr — View Citation

Rabant M, Amrouche L, Lebreton X, Aulagnon F, Benon A, Sauvaget V, Bonifay R, Morin L, Scemla A, Delville M, Martinez F, Timsit MO, Duong Van Huyen JP, Legendre C, Terzi F, Anglicheau D. Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvas — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Death-censored graft loss	Return to dialysis or re-transplant	2 weeks-12 months post-transplant
Primary	Clinical indication biopsy-proven acute rejection	Clinical rejection, Banff criteria	2 weeks-12 months post-transplant
Primary	De novo donor specific antibody development	De novo human leukocyte antibody (HLA) antibodies, donor specific	2 weeks-12 months post-transplant
Primary	Subclinical tubulitis	Subclinical rejection, Banff criteria	12-month study exit biopsy
Primary	Interstitial fibrosis and inflammation (IFTA + i)	IFTA + i, defined by Mayo criteria	12-month study exit biopsy
Secondary	Renal allograft function	Change in eGFR (slope, ?) and graft function (eGFR) (absolute, mL/min)	6, 12, 24 and 60 months post-transplant
Secondary	Microvascular inflammation	Banff ptc, g, c4d, cg	12-month study exit biopsy
Secondary	Development IFTA from implantation to 12-months	Banff ? ci, ct, cv	12-month study exit biopsy
Secondary	Days from transplantation to clinical-biopsy proven rejection	Time to biopsy proven rejection	2 weeks-12 months post-transplant
Secondary	Albuminuria >300mg/day	Urine albumin: Cr ratio	6, 12, 24 and 60 months post-transplant
Secondary	Cost-effectiveness of urine CXCL10 monitoring strategy	Costs of urine CXCL10 screening	2 weeks-12 months post-transplant
Secondary	Quality of life	EuroQOL (EQ-5DL)	6 and 12 months post-transplant
Secondary	Urine CXCL10 kinetics	Change in urine CXCL10 levels in response to rejection therapy	2 weeks-12 months post-transplant