Clinical trial NCT05423496: KidneyCare Immuno-optimization in Renal Allografts (KIRA)
Official title: KidneyCare Immuno-optimization in Renal Allografts
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Kidney Transplant
Immunosuppression
Allograft
Keywords: 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
AlloSue
AlloMap
iBox
Gene expression profiling
HistoMap assay
Immune optimization
Lead sponsor: CareDx
Sponsor class: INDUSTRY
First posted: 2022-06-21
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Participant is willing and able to give informed consent for participation in the trial
2. Patients aged 18 years or older
3. cPRA \<20% \& no preformed DSA at time of transplant (using center-specific threshold)
4. Recipient (or planned recipient, if pre-transplant) of single, first-time, deceased (DBD/DCD) or living donor Kidney Transplant
5. Planned post-transplant maintenance immunosuppression regimen consisting of tacrolimus and MMF, with or without prednisone
6. Negative virtual crossmatch (performed by transplant center)
7. Female participants of childbearing potential must be willing to ensure that they or their partner use effective contraception during the trial
8. 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:

1. Female participant who is pregnant, lactating, or planning pregnancy during the trial
2. Preformed DSA or ABO incompatible transplant
3. Chronic oral steroid use (for any reason)
4. Planned post-transplant immunosuppression regimen utilizing cyclosporine, azathioprine, mTOR inhibitors, and/or co-stimulatory blockers
5. Donor organ from identical twin or history of prior kidney transplant
6. Multivisceral transplant (heart/kidney, kidney/pancreas, liver/kidney, etc.) or history of hematopoietic stem cell transplant
7. 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)
8. 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
9. Participants who are currently or have previously participated in another research trial involving an investigational drug/product in the past 12 weeks
10. 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:

1. Maintenance immunosuppression that includes cyclosporine, azathioprine, mTOR inhibitors, and/or co-stimulatory blockers
2. Baseline proteinuria ≥0.5g/day (confirmed by repeat measurement)
3. Baseline eGFR \<45mL/min (average of 3 most recent prior readings)
4. Any episodes of biopsy-proven acute rejection (TCMR ≥1A or ABMR) since the time of transplant
5. Any interval detection of de novo DSA since the time of transplant (per center-specific threshold)
6. AlloSure result \>0.5% at Month 3

Primary outcomes:
measure: Estimated glomerular filtration rate (eGFR) at 12 months, non-inferiority
timeFrame: 12 months
measure: Estimated glomerular filtration rate (eGFR) at 24 months, non-inferiority
timeFrame: 24 months
measure: Interstitial fibrosis/tubular atrophy (IF/TA) quantified by Banff Working Group biopsy grade(s) at 12-months post-transplant
timeFrame: 12 months
measure: Interstitial fibrosis/tubular atrophy (IF/TA) quantified by Banff Working Group biopsy grade(s) at 24-months post-transplant
timeFrame: 24 months
measure: Transplant glomerulopathy (TG) at 12-months post-transplant, quantified by biopsy-based histopathology grade(s)
timeFrame: 12 months
measure: Transplant glomerulopathy (TG) at 24-months post-transplant, quantified by biopsy-based histopathology grade(s)
timeFrame: 24 months
measure: Total number of biopsies performed post-transplant, including both surveillance and clinically indicated biopsies
timeFrame: 24 months
measure: Number of clinically indicated biopsies planned and performed in the first 12- months post- transplant
timeFrame: 12 months
measure: Number of clinically indicated biopsies planned and performed in the 24-months post- transplant
timeFrame: 24 months
Secondary outcomes:
measure: 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.
timeFrame: 24 months
measure: Results of DSA testing, performed as outlined in the testing schedule
timeFrame: 24 months
Other outcomes:
measure: Incidence of clinically-relevant infections among study participants (defined as infection requiring inpatient admission for evaluation/treatment)
timeFrame: 24 months
measure: Correlation between longitudinal AlloMap Kidney Scores / iBox Results and dosing of immunosuppressive agents
timeFrame: 24 months
measure: Correlation between longitudinal AlloMap Kidney Scores / iBox Results and eFGR.
timeFrame: 24 months
measure: Correlation between longitudinal AlloMap Kidney Scores / iBox Results and dnDSA rate.
timeFrame: 24 months
measure: Correlation between cross-sectional AlloMap Kidney Scores / iBox Results and rejection (TCMR, ABMR) on histology from for-cause & surveillance biopsies.
timeFrame: 24 months
measure: Correlation between cross-sectional AlloMap Kidney Scores / iBox Results and severity/grading of transplant glomerulopathy and IFTA on for-cause & surveillance biopsies
timeFrame: 24 months
measure: Immunosuppression Dosing
timeFrame: 24 months
measure: Immunosuppression Exposure
timeFrame: 24 months
measure: Incidence of viremia ( including BK & CMV), defined as copies/mL in excess of the limit of detection
timeFrame: 24 months
measure: PCR viral load over time (defined as time to resolution after initial identification of infection)
timeFrame: 24 months
measure: Incidence of any associated end-organ manifestations of viral infection
timeFrame: 24 months
measure: Changes in immunosuppression, defined as the change in the median daily dose (mg/day) of immunosuppressive agents
timeFrame: 24 months
measure: Incidence of proteinuria, defined by urine protein to creatinine ratio >0.5g/g, confirmed on serial samples
timeFrame: 24 months
measure: 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
timeFrame: 24 months
Locations:
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