Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients

Study Overview
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Brief Summary
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Objective: Investigate the direct correlation of CYP3A5 genotype with tacrolimus trough levels and clinical outcomes. The primary endpoint of this study is to evaluate the proportion of patients reaching target levels (8-10 ng/mL) on Day 3 and Day 7 after kidney transplantation.

Detailed Description
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Participants: All new kidney transplant recipients aged 18 to 65 years who are admitted at UNC-CH and provided informed consent will be included in this study (Unless they meet the exclusion criteria specified). A total of an anticipated 260 subjects will be included in the study, 130 of which will be included in the pharmacogenomic group and the remaining 130 will be in the control group. Procedures (methods): The pharmacogenomic group will partake in a 12-month study comprising of two periods, Genotype-Guided Initial Dosing Intervention and Follow-up. Briefly, patients on transplant waitlist will be screened for eligibility. At the pre-intervention assessment (Study Day 0), buccal swab samples for genotyping will be collected on all eligible patients who provided informed consent (performed in real time). Results of the genotyping test will be incorporated into electronic medical record (EMR). The initial tacrolimus dose will be based on genotype: 0.1 mg/kg/day (non- expressers) or 0.2 mg/kg/day, with maximum of 20 mg/day (expressers) given in 2 divided doses. Eligible patients who consented to receive genotype-guided tacrolimus dose will enter the pharmacogenomic group and will receive the initial tacrolimus dosing based on genotype results following kidney transplantation (Study Day 1). Subsequent tacrolimus dosing will then be adjusted according to trough concentrations (C0) and therapeutic target concentrations. The genotype-guided dosing recommendation for tacrolimus only refers to the initial tacrolimus dose. All patients in the pharmacogenomic group will be followed from Study Day 2 and up to 12 months to assess long-term outcome. Age-, race-, and disease-matched patients who had previously received kidney transplantation with standard tacrolimus dosing from 2010 to present will also be asked to give consent for genotyping (historical controls). These patients will be included in the control group and their safety and efficacy data will be collected retrospectively for up to 12 months from the initiation of first tacrolimus dose. As there are confounding variables, including age, race and disease state that may impact the results of the study, our study design incorporates an overall matching strategy, so that we can identify a well-matched control group. First, to control for differences in care over time, patients in the pharmacogenomic group will be matched to controls enrolled from 2010 to present. This time period was selected as there had been no major changes in standard of care or treatment regimen since 2010. After eligibility is met, control patients will be selected to match the pharmacogenomic group using a computerized matching algorithm that has been optimized to match baseline demographic and disease characteristics that have been identified a priori as likely to influence the treatment response to tacrolimus. To balance the trade-off between minimizing bias and maximizing matched sample size, a systematic approach will be conducted to identify the number of matched control patients for each patient in the pharmacogenomic group. This approach will include the following steps: 1) run the desired matching algorithm, starting with 1:1 (one control to one patient in the pharmacogenomic group) matching and iterating until the maximum desired number of potential controls per treated subject is reached; 2) for each iteration, test for covariate balance; and (3) generate numeric summaries and graphical plots of the balance statistics across all iterations in order to determine the optimal number. The selection of patients for the control group using a matching algorithm will be conducted by an independent statistician in a blinded and unbiased manner. The statistician will have no knowledge of survival outcome, other outcome data, and genotype. The algorithm will not be used to guide treatment in any way.

Official Title
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Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients

Conditions
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Renal Transplant

Intervention / Treatment
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* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All new kidney transplant recipients aged 18 to 65 years who are admitted at UNC-CH and provided informed consent will be included in this study. Exclusion Criteria: - Patients will be excluded from participating in the study to receive genotype-guided tacrolimus dosing if he/she meets any of the exclusion criteria described below. Recipients who did not consent to participate in the study. Highly sensitized patients (ie, pretransplant T or B cell flow crossmatch positive) Recipients of ABO incompatible kidney transplant Recipients with preformed donor-specific antibodies (DSA) Human Leukocyte Antigen (HLA) identical kidney transplant Recipients of non-kidney transplant Recipients of repeat transplant if they are on immunosuppression at the time of transplant Patients using medications that have known pharmacokinetic (PK) drug interaction with tacrolimus Patients in whom tacrolimus therapy is contraindicated

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYP3A5 based tacrolimus dosing<br>Subjects in this treatment arm will receive initial tacrolimus based on their genotype i.e., CYP3A5*1/*1 and CYP3A5*1/*3 (Expressers) will receive the initial tacrolimus dose of 0.2 mg/kg/day, with maximum of 20 mg/day in 2 divided doses. For CYP3A5*3/*3 (Non-Expressers), the subjects will receive initial tacrolimus dose of 0.1 mg/kg/day in 2 divided doses. | Drug: Tacrolimus<br>* See description in arm/group sections<br>* Other names: Prograf, Advagraf;|
| No Intervention: Control<br>Subjects in the prospective control group will receive standard tacrolimus dosing as recommended per package insert and will not be dosed based on their genotype. Similarly, subjects that underwent renal transplant after 2010 and received standard tacrolimus dosing (per package insert) will serve as historical controls. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation |  | Day 3 after transplantation | 
| Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation |  | Day 7 after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Events of Biopsy Proven Acute Rejection (BPAR) | The number of events of BPAR within the first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation | first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation | 
| Tacrolimus Level | Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL) | 4 months | 
| Mean Number of Dose Adjustments and/or Drug Alterations | Mean number of dose adjustments and/or drug alteration or addition due to insufficient immunosuppression. | 12 months | 
| Percent of Participants With Chronic Renal Impairment by eGFR Category | Renal function will be assessed using estimated Glomerular Filtration Rate (eGFR). Creatinine clearance (CrCl) may also be calculated as a reference. Patients will be categorized as having either mild (eGFR of 60 mL/min/1.73m^2 to 89 mL/min/1.73m^2), moderate (eGFR of 30 mL/min/1.73m^2 to 59 mL/min/1.73m^2), or severe renal impairment (eGFR <30 mL/min/1.73m^2). | 12 months | 
| Number of Adverse Outcomes | Number of adverse outcomes (i.e., graft loss, infection, and death) | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UNC, Renal Transplant, Tacrolimus, Phase IV