AIIM Trial: Personalized Medicine Approach to Kidney Allograft Function

Study Overview
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Brief Summary
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The objective of the proposed study it to perform a pilot clinical trial both to establish feasibility of applying a computational, augmented intelligence based approach, Phenotypic Precision Medicine (PPM), to optimizing combination drug therapy and to gather preliminary data to support a larger fully powered multi-center clinical trial. The key rationale for this clinical selection is that we have the technical, biological, and medical expertise in this disease, a wealth of experience in the use of PPM in both in vitro and the clinical setting, and a robust and integrated transplant program with a well-functioning clinical trial infrastructure.

Detailed Description
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In this pilot/feasibility trial the investigators will assess the feasibility of the trial design described below and perform a pilot study to obtain information for the design of a future multicenter randomized controlled trial (RCT). These goals will be achieved within the three year span of this program. The study has organized the investigator team to be able to achieve the following goals: 1) obtain regulatory approval, 2) optimize the clinical trial design, 3) recruit patients, 4) conduct the study, including optimization of immunosuppression regimen and monitoring the endpoints of interest, 5) conduct statistical analysis of the results, and 6) analyze the findings. Thirty-four subjects will be recruited at the time of kidney transplantation. Inclusion and exclusion criteria are listed below. All subjects will be started with institutional standard of care (SOC): quadruple immunosuppressive therapy with in-duction (basiliximab or antithymocyte globulin), tacrolimus, steroids, and mycophenolate mofetil/mycophenolic acid (MMF/MPA). Maintenance immunosuppression after transplantation will also be determined by the center per SOC. At recruitment, one month after transplantation, subjects without biopsy proven rejection will be recruited and enrolled in the baseline monitoring period of the study. Monitoring includes weekly dd-cfDNA (donor-derived cell-free DNA) measurements, drawn at the same time as SOC labs, up to three months after transplantation. Subjects will continue to be seen per clinical SOC Both SOC and dd-cfDNA labs will be obtained per patient preference (commercial lab, mobile phlebotomy, or at UF). Dd-cfDNA assessments will be performed at a Clinical Laboratory Improvement Amendments (CLIA)-approved centralized location per company standards. Clinical SOC includes an updated history and physical, including a full medication history, biochemical and hematological measurements, and drug exposure of tacrolimus monitored by obtaining trough level measurements. Three months after transplantation, a graft biopsy will be obtained and analyzed by an expert renal pathologist. Patients with evidence of rejection on biopsy will be excluded. Patients without rejection (Banff Classification 2018 active or chronic cellular or antibody mediated rejection) will undergo balanced randomization (1:1) to one of the following treatment arms: Control arm: Subjects will continue per SOC, where the management of their immunosuppression regimen will be determined by their physician per center practices, including dd-cfDNA data. Treatment arm: Subjects will have dd-cfDNA data analyzed by PPM. Data, such as drug levels and regimens, will be used to fit a 2nd order polynomial for each patient to build patient-specific dose-response pro-files with covariates that include the administered drugs tacrolimus, steroids, and MMF/MPA. PPM will be used to derive an optimal combination of tacrolimus, MMF/MPA, and prednisone to achieve minimal renal allograft injury, while staying within the therapeutic range of the medications. All else being equal, the most efficacious combination with the lowest dose of tacrolimus will be utilized. In either arm, if a change is made in the immunosuppression regimen, SOC and dd-cfDNA labs will be obtained one week later to assess for changes and for the regimen to be adjusted accordingly. If no change is made in the immunosuppression regimen, the subject will continue with their SOC labs and clinic visit schedule. All subjects will undergo a protocol biopsy at the completion of the study at 15 months (12 months after first biopsy).

Official Title
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AIIM Trial: Protecting Kidney Function After Transplantation Using Augmented Intelligence Based Immunosuppression Dosing

Conditions
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Kidney Transplant Rejection

Intervention / Treatment
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* Other: Phenotypic Personalized Medicine Dosing
* Other: Phenotypic Personalized Medicine Dosing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (18 years of age or older) patients with end-stage renal disease (ESRD) Recipient of a first or subsequent deceased donor kidney transplant Clinical indication to receive tacrolimus as the primary immunosuppression Willing and able to provide written informed consent to participate Exclusion Criteria: Recipients of transplanted organs other than kidney Recipients of a transplant from a monozygotic (identical) sibling Human Leukocyte Antigen (HLA)-identical donor (zero out of six antigen mismatch donor) Recipient of third or more transplant Current or historical panel reactive antibodies of more than 50% Blood Type (ABO) incompatibility or known moderate or strong donor specific antibodies De novo or recurrent glomerulonephritis on 3-month biopsy Lupus nephritis on 3-month biopsy Focal segmental glomerulosclerosis on 3-month biopsy BK polyomavirus nephropathy in current or prior transplant Recipient of a bone marrow transplant Recipient who is pregnant Enrollment in a competing trial that would interfere with selection or alteration of immunosuppression Inability to follow up with transplant center for up to 15 months after transplantation Anticipated major surgery during the time of planned study Major medical illness with life expectancy less than 15 months Suspicion of noncompliance Anticipated relocation to a location that would not allow follow up at local center in the next 18 months Inability to tolerate normal range levels of tacrolimus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Physician Dosing<br>Subjects will continue per SOC, where the management of their immunosuppression regimen will be determined by their physician per center practices, including dd-cfDNA data. | Other: Phenotypic Personalized Medicine Dosing<br>* Phenotypic Personalized Medicine (PPM) will mediate mechanism-independent and patient specific optimization of immunosuppression. We have developed a powerful platform that allows the provider to use clinical data to construct a Parabolic Response Surface (PRS). Using this visualization of the data, the provider can them make a decision on the optimal combination of drug doses needed to achieve the desired outcome.<br>|
| Experimental: PPM Dosing<br>Subjects will have dd-cfDNA data analyzed by PPM. Data, such as drug levels and regimens, will be used to fit a 2nd order polynomial for each patient to build patient-specific dose-response profiles with covariates that include the administered drugs tacrolimus, steroids, and MMF/MPA. PPM will be used to derive an optimal combination of tacrolimus, MMF/MPA, and prednisone to achieve minimal renal allograft injury, while staying within the therapeutic range of the medications. All else being equal, the most efficacious combination with the lowest dose of tacrolimus will be utilized. | Other: Phenotypic Personalized Medicine Dosing<br>* Phenotypic Personalized Medicine (PPM) will mediate mechanism-independent and patient specific optimization of immunosuppression. We have developed a powerful platform that allows the provider to use clinical data to construct a Parabolic Response Surface (PRS). Using this visualization of the data, the provider can them make a decision on the optimal combination of drug doses needed to achieve the desired outcome.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in renal allograft interstitial fibrosis (IF) between 3-month baseline up to 15-month follow-up. | Multiple studies have used this outcome because it 1) correlates well with renal function as measured by Creatinine Clearance (CrCl), 2) is a quantitative, continuous, and objective measure, thus needing fewer subjects to show a difference between groups in a small study, and 3) it is less susceptible to acute fluctuations than CrCl and more reflective of chronic injury. Renal allograft IF is a continuous variable that ranges from 0 to 100%. | Change from 3-month baseline to 15-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Creatinine Clearance |  | Change from 3-month baseline to 15-month follow-up | 
| Change in tubular atrophy and vacuolization on biopsy | Used as markers of allograft function and chronic allograft injury. | Change from 3-month baseline to 15-month follow-up | 
| 24-hour proteinuria | This would be performed using a 24-hour urine collection method for the greatest accuracy. | Change from 3-month baseline to 15-month follow-up | 
| Cumulative tacrolimus exposure | Measured by a summation of total tacrolimus dose over the 12 months of study dosing and by the integration of the cumulative tacrolimus trough levels over the study period. | At 15-month follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney, Transplant, dd-cf DNA, Personalized Medicine