KidneyCare Immuno-optimization in Renal Allografts (KIRA)

Study Overview
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Brief Summary
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This is an unblinded, randomized, four-arm interventional research study enrolling patients who are undergoing kidney transplantation. The aim of the study is to determine whether patients at low risk of rejection can safely reduce the doses of their post-transplant immunosuppression medications using a combination of tests that include donor-specific antibodies (DSA), histology (looking at tissue from the donor graft), and donor-derived cell-free DNA (AlloSure). Eligible participants will be randomized in a 2:1 ratio into one of two immune-optimization (intervention) arms or the corresponding observational (control) arms. Two thirds of the participants in the study will have their decision to reduce immunosuppression made based on these test results and the other third will have the decision made based on standard of care clinical assessment and laboratory testing. The study will include two additional parameters under investigation - the AlloMap Kidney gene expression profiling test and the iBox prediction algorithm, but these will not be actively used to make any decisions as part of the trial. AlloSure, AlloMap Kidney, and iBox are the three components of the KidneyCare panel developed by CareDx.

Detailed Description
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This is a prospective, multicenter, open-label randomized controlled four-arm interventional trial of kidney transplant recipients receiving KidneyCare (AlloSure-Kidney, AlloMap Kidney, and iBox) surveillance testing. Eligible patients who meet inclusion/exclusion criteria and provide consent will undergo standard immune induction per their center protocol and begin a post-transplant maintenance regimen of tacrolimus and mycophenolate mofetil (MMF), with or without steroids after transplantation. If all prerequisite criteria are satisfied at 3 months, participants will be randomized and participants in the intervention arms will begin protocolized immuno-optimization, with the objective of the study being the gradual elimination of one immunosuppressive agent (either MMF or steroids) and optimization of calcineurin inhibitors (CNI) dosing. Any immune optimization changes in the control/observational arms will occur based on clinician discretion.

Official Title
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KidneyCare Immuno-optimization in Renal Allografts

Conditions
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Kidney Transplant, Immunosuppression, Allograft

Intervention / Treatment
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* Diagnostic Test: KidneyCare
* Drug: steroid
* Drug: MMF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is willing and able to give informed consent for participation in the trial Patients aged 18 years or older cPRA <20% & no preformed DSA at time of transplant (using center-specific threshold) Recipient (or planned recipient, if pre-transplant) of single, first-time, deceased (DBD/DCD) or living donor Kidney Transplant Planned post-transplant maintenance immunosuppression regimen consisting of tacrolimus and MMF, with or without prednisone Negative virtual crossmatch (performed by transplant center) Female participants of childbearing potential must be willing to ensure that they or their partner use effective contraception during the trial In the Investigator's opinion, is able and willing to comply with all trial requirements Exclusion Criteria: The participant may not enter the trial if ANY of the following apply: Female participant who is pregnant, lactating, or planning pregnancy during the trial Preformed DSA or ABO incompatible transplant Chronic oral steroid use (for any reason) Planned post-transplant immunosuppression regimen utilizing cyclosporine, azathioprine, mTOR inhibitors, and/or co-stimulatory blockers Donor organ from identical twin or history of prior kidney transplant Multivisceral transplant (heart/kidney, kidney/pancreas, liver/kidney, etc.) or history of hematopoietic stem cell transplant Participant with life expectancy of less than 6 months or is inappropriate for immuno-optimization (including those patients at increased risk of primary disease recurrence w/ reduction in post-transplant immunosuppression) Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the trial, or may influence the result of the trial, or the participant's ability to participate in the trial Participants who are currently or have previously participated in another research trial involving an investigational drug/product in the past 12 weeks Any condition that would preclude protocol biopsies (e.g. patients on lifelong anticoagulation for whom anticoagulation cannot be safely held) Randomization Criteria (assessed at 3 months) The participant may not proceed with randomization if ANY of the following apply: Maintenance immunosuppression that includes cyclosporine, azathioprine, mTOR inhibitors, and/or co-stimulatory blockers Baseline proteinuria ≥0.5g/day (confirmed by repeat measurement) Baseline eGFR <45mL/min (average of 3 most recent prior readings) Any episodes of biopsy-proven acute rejection (TCMR ≥1A or ABMR) since the time of transplant Any interval detection of de novo DSA since the time of transplant (per center-specific threshold) AlloSure result >0.5% at Month 3

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Steroid Control Arm<br>133 patient undergoing KidneyCare Surveillance with Immune optimization at clinician discretion | Diagnostic Test: KidneyCare<br>* Using KidneyCare platform as a tool to successfully augment immunosuppressant agents through regular surveillance allowing minimization of doses and number of agents.<br>|
| Experimental: Steroid Immuno-optimization Arm<br>267 patient undergoing KidneyCare Surveillance with protocolized AlloSure-guided immuno-optimization of steroids/CNI | Diagnostic Test: KidneyCare<br>* Using KidneyCare platform as a tool to successfully augment immunosuppressant agents through regular surveillance allowing minimization of doses and number of agents.<br>Drug: steroid<br>* optimization of steroids<br>|
| Active Comparator: Tacrolimus and mycophenolate mofetil (MMF) Control Arm<br>133 patient undergoing KidneyCare Surveillance with Immune optimization at clinician discretion | Diagnostic Test: KidneyCare<br>* Using KidneyCare platform as a tool to successfully augment immunosuppressant agents through regular surveillance allowing minimization of doses and number of agents.<br>|
| Experimental: MMF Immuno-optimization Arm<br>267 patient undergoing KidneyCare Surveillance with protocolized AlloSure-guided immuno-optimization of MMF/CNI | Diagnostic Test: KidneyCare<br>* Using KidneyCare platform as a tool to successfully augment immunosuppressant agents through regular surveillance allowing minimization of doses and number of agents.<br>Drug: MMF<br>* optimization of MMF<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated glomerular filtration rate (eGFR) at 12 months, non-inferiority | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (safety endpoint) | 12 months | 
| Estimated glomerular filtration rate (eGFR) at 24 months, non-inferiority | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (safety endpoint) | 24 months | 
| Interstitial fibrosis/tubular atrophy (IF/TA) quantified by Banff Working Group biopsy grade(s) at 12-months post-transplant | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (safety) | 12 months | 
| Interstitial fibrosis/tubular atrophy (IF/TA) quantified by Banff Working Group biopsy grade(s) at 24-months post-transplant | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (safety) | 24 months | 
| Transplant glomerulopathy (TG) at 12-months post-transplant, quantified by biopsy-based histopathology grade(s) | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (safety) | 12 months | 
| Transplant glomerulopathy (TG) at 24-months post-transplant, quantified by biopsy-based histopathology grade(s) | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (safety) | 24 months | 
| Total number of biopsies performed post-transplant, including both surveillance and clinically indicated biopsies | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (efficacy) | 24 months | 
| Number of clinically indicated biopsies planned and performed in the first 12- months post- transplant | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (efficacy) | 12 months | 
| Number of clinically indicated biopsies planned and performed in the 24-months post- transplant | Demonstrate the safety and efficacy of KidneyCare as tool to successfully adjust immunosuppressant agents using regular surveillance for safe drug minimization. (efficacy) | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Histological assessment of tissue biopsy with paired AlloSure dd-cfDNA result - performed both 'For Cause' and 'Surveillance', using standard biopsy and HistoMap molecular assessment using nCounter. | Identify correlation between dd-cfDNA and histopathological allograft rejection based on all clinical biopsies. | 24 months | 
| Results of DSA testing, performed as outlined in the testing schedule | Compare rates of de-novo DSA antibody formation in immuno-optimization and control groups. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AlloSue, Calcineurin inhibitors, allograft loss and survival, Chronic immunosuppression, Steroid avoidance, Low-risk kidney transplant recipients, Acute rejection, KidneyCare, Immunological risk assessment, Cross-match testing, Donor-specific antibodies, Donor-derived cell-free DNA, AlloMap, iBox, Gene expression profiling, HistoMap assay, Immune optimization