Clinical trial NCT03020589: Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients
Official title: Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Renal Transplant
Keywords: Renal Transplant
Tacrolimus
UNC
Phase IV
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
First posted: 2017-01-13
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation
timeFrame: Day 3 after transplantation
measure: Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation
timeFrame: Day 7 after transplantation
Secondary outcomes:
measure: Number of Events of Biopsy Proven Acute Rejection (BPAR)
timeFrame: first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation
measure: Tacrolimus Level
timeFrame: 4 months
measure: Mean Number of Dose Adjustments and/or Drug Alterations
timeFrame: 12 months
measure: Percent of Participants With Chronic Renal Impairment by eGFR Category
timeFrame: 12 months
measure: Number of Adverse Outcomes
timeFrame: 12 months
Other outcomes:
measure: Direct and Indirect Costs
timeFrame: 12 months
Locations:
city: Chapel Hill
country: United States
facility: Univeristy of North Carolina
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Alexander Toledo, MD
role: PRINCIPAL_INVESTIGATOR
References: