Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients
Condition: Renal Transplant
Study type: Interventional
Phase: Phase 4

Summary: 
      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: 
      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.
    

Intervention name(s): Tacrolimus
Intervention type(s): Drug
Intervention description(s): See description in arm/group sections
Other intervention name(s): Prograf, Advagraf
Intervention MeSH terms: Tacrolimus
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Renal Transplant; Tacrolimus; UNC; Phase IV