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Business decision based on clinical utility considerations
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Steroid Control Arm | Active Comparator | 133 patient undergoing KidneyCare Surveillance with Immune optimization at clinician discretion |
|
| Steroid Immuno-optimization Arm | Experimental | 267 patient undergoing KidneyCare Surveillance with protocolized AlloSure-guided immuno-optimization of steroids/CNI |
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| Tacrolimus and mycophenolate mofetil (MMF) Control Arm | Active Comparator | 133 patient undergoing KidneyCare Surveillance with Immune optimization at clinician discretion |
|
| MMF Immuno-optimization Arm | Experimental | 267 patient undergoing KidneyCare Surveillance with protocolized AlloSure-guided immuno-optimization of MMF/CNI |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| KidneyCare | Diagnostic Test | Using KidneyCare platform as a tool to successfully augment immunosuppressant agents through regular surveillance allowing minimization of doses and number of agents. |
| 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) |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of clinically-relevant infections among study participants (defined as infection requiring inpatient admission for evaluation/treatment) | Assessment of all medical events throughout the duration of the study. | 24 months |
| Correlation between longitudinal AlloMap Kidney Scores / iBox Results and dosing of immunosuppressive agents |
Inclusion Criteria:
Exclusion Criteria:
The participant may not enter the trial if ANY of the following apply:
Randomization Criteria (assessed at 3 months)
The participant may not proceed with randomization if ANY of the following apply:
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| ID | Term |
|---|---|
| D013256 | Steroids |
| ID | Term |
|---|---|
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
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| steroid | Drug | optimization of steroids |
|
| MMF | Drug | optimization of MMF |
|
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 |
| 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 |
Assess utility of AlloMap Kidney and iBox results for purposes of immuno-optimization and post-transplant surveillance |
| 24 months |
| Correlation between longitudinal AlloMap Kidney Scores / iBox Results and eFGR. | Assess utility of AlloMap Kidney and iBox results for purposes of immuno-optimization and post-transplant surveillance | 24 months |
| Correlation between longitudinal AlloMap Kidney Scores / iBox Results and dnDSA rate. | Assess utility of AlloMap Kidney and iBox results for purposes of immuno-optimization and post-transplant surveillance | 24 months |
| Correlation between cross-sectional AlloMap Kidney Scores / iBox Results and rejection (TCMR, ABMR) on histology from for-cause & surveillance biopsies. | Assess utility of AlloMap Kidney and iBox results for purposes of immuno-optimization and post-transplant surveillance | 24 months |
| Correlation between cross-sectional AlloMap Kidney Scores / iBox Results and severity/grading of transplant glomerulopathy and IFTA on for-cause & surveillance biopsies | Assess utility of AlloMap Kidney and iBox results for purposes of immuno-optimization and post-transplant surveillance | 24 months |
| Immunosuppression Dosing | Comparison of cumulative immunosuppression exposure in each arm (average daily dose over time) | 24 months |
| Immunosuppression Exposure | Comparison of final dosage of each immunosuppressive agent at the conclusion of the study in each arm (tacrolimus, mycophenolate/Myfortic, prednisone) | 24 months |
| Incidence of viremia ( including BK & CMV), defined as copies/mL in excess of the limit of detection | Assessment of all medical events throughout the duration of the study | 24 months |
| PCR viral load over time (defined as time to resolution after initial identification of infection) | Assessment of all medical events throughout the duration of the study | 24 months |
| Incidence of any associated end-organ manifestations of viral infection | Assessment of all medical events throughout the duration of the study | 24 months |
| Changes in immunosuppression, defined as the change in the median daily dose (mg/day) of immunosuppressive agents | Assessment of all medical events throughout the duration of the study | 24 months |
| Incidence of proteinuria, defined by urine protein to creatinine ratio >0.5g/g, confirmed on serial samples | Assessment of all medical events throughout the duration of the study | 24 months |
| Number of clinically defined and/or biopsy-confirmed allograft rejection events, including the specific histologic diagnosis made, and if treated, description and duration of therapeutic regimen | Assessment of all medical events throughout the duration of the study | 24 months |