Clinical trial NCT03206801: Urine CXCL10 Monitoring Trial in Kidney Transplant
Official title: A Randomized Controlled Trial of Urine CXCL10 Chemokine Monitoring Post-renal Transplant
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Kidney Transplant; Complications
Rejection of Renal Transplant
Keywords: Urine biomarker
CXCL10 chemokine
Post-transplant monitoring
Protocol biopsy
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Canadian National Transplant Research Program
First posted: 2017-07-02
Enrollment: 420
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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).
Primary purpose: SCREENING

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Death-censored graft loss
timeFrame: 2 weeks-12 months post-transplant
measure: Clinical indication biopsy-proven acute rejection
timeFrame: 2 weeks-12 months post-transplant
measure: De novo donor specific antibody development
timeFrame: 2 weeks-12 months post-transplant
measure: Subclinical tubulitis
timeFrame: 12-month study exit biopsy
measure: Interstitial fibrosis and inflammation (IFTA + i)
timeFrame: 12-month study exit biopsy
Secondary outcomes:
measure: Renal allograft function
timeFrame: 6, 12, 24 and 60 months post-transplant
measure: Microvascular inflammation
timeFrame: 12-month study exit biopsy
measure: Development IFTA from implantation to 12-months
timeFrame: 12-month study exit biopsy
measure: Days from transplantation to clinical-biopsy proven rejection
timeFrame: 2 weeks-12 months post-transplant
measure: Albuminuria >300mg/day
timeFrame: 6, 12, 24 and 60 months post-transplant
measure: Cost-effectiveness of urine CXCL10 monitoring strategy
timeFrame: 2 weeks-12 months post-transplant
measure: Quality of life
timeFrame: 6 and 12 months post-transplant
measure: Urine CXCL10 kinetics
timeFrame: 2 weeks-12 months post-transplant
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Winnipeg
country: Canada
facility: University of Manitoba, Transplant Manitoba Adult Kidney Program
state: Manitoba
city: London
country: Canada
facility: Western University
state: Ontario
city: Ottawa
country: Canada
facility: University of Ottawa
state: Ontario
city: Toronto
country: Canada
facility: University Health Network, University of Toronto
state: Ontario
city: Montreal
country: Canada
facility: McGill
state: Quebec
city: Montréal
country: Canada
facility: Centre de recherche du CHUM (CRCHUM)
state: Quebec
city: Québec City
country: Canada
facility: Université Laval
state: Quebec
Study officials:
affiliation: University of Manitoba
name: Julie Ho, MD
role: PRINCIPAL_INVESTIGATOR
References:
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: 10.1097/TP.0b013e31822d4de1.
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 setting. Am J Transplant. 2012 Jul;12(7):1811-23. doi: 10.1111/j.1600-6143.2012.03999.x. Epub 2012 Mar 5.
citation: 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.0000000000000419.
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.0000000000000537. eCollection 2015 Sep.
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.
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.0000000000000589. eCollection 2016 Jun.
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 Mar;100(3):648-54. doi: 10.1097/TP.0000000000000867.
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 transplant injury. Am J Transplant. 2013 Oct;13(10):2634-44. doi: 10.1111/ajt.12426. Epub 2013 Aug 22.
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 Noninvasive Diagnosis of Antibody-Mediated Kidney Allograft Rejection. J Am Soc Nephrol. 2015 Nov;26(11):2840-51. doi: 10.1681/ASN.2014080797. Epub 2015 May 6.
citation: Ho J, Sharma A, Kroeker K, Carroll R, De Serres S, Gibson IW, Hirt-Minkowski P, Jevnikar A, Kim SJ, Knoll G, Rush DN, Wiebe C, Nickerson P. Multicentre randomised controlled trial protocol of urine CXCL10 monitoring strategy in kidney transplant recipients. BMJ Open. 2019 Apr 11;9(4):e024908. doi: 10.1136/bmjopen-2018-024908.