A Phase 4 interventional study of Tacrolimus in Renal Transplant, sponsored by University of North Carolina, Chapel Hill. Completed at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2023-06-26.
Sponsored by University of North Carolina, Chapel Hill · Phase 4, Interventional, and Treatment
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.
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.
University of North Carolina, Chapel Hill is the lead sponsor of 1,340 studies on the registry; 133 are open to participants now.
Of its 155 completed or terminated interventional studies of FDA-regulated products, 136 (88%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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
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.
See description in arm/group sections
Also known as: Prograf, Advagraf
Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation
Time frame: Day 3 after transplantation
Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation
Time frame: Day 7 after transplantation
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
Time frame: 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)
Time frame: 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.
Time frame: 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).
Time frame: 12 months
Number of Adverse Outcomes
Number of adverse outcomes (i.e., graft loss, infection, and death)
Time frame: 12 months
Direct and Indirect Costs
Direct and indirect cost related to treatment and management kidney transplant recipients
Time frame: 12 months
| Milestone | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Started | 40 | 57 |
| Completed | 40 | 57 |
| Not completed | 0 | 0 |
| proportion of participants | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation | 0.2 | 0.14 |
| Proportion of participants | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation | 0.29 | 0.21 |
The number of events of BPAR within the first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation
| BPAR events | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Days 0 through 90 | 3 | 2 |
| Days 91-180 | 3 | 0 |
| Days 181-365 | 0 | 0 |
Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL)
| Days | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Tacrolimus Level | 6.4 ± 5.96 | 7.87 ± 5.35 |
Mean number of dose adjustments and/or drug alteration or addition due to insufficient immunosuppression.
| Adjustments | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Mean Number of Dose Adjustments and/or Drug Alterations | 7.86 ± 2.5 | 7.37 ± 2.7 |
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).
| percentage of participants | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Mild : Week 1 | 23 | 24 |
| Mild : Month12 | 53 | 46 |
| Moderate : Week 1 | 35 | 42 |
| Moderate : Month12 | 33 | 51 |
| Severe : Week 1 | 43 | 35 |
| Severe : Month12 | 13 | 3 |
Number of adverse outcomes (i.e., graft loss, infection, and death)
| adverse outcomes | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Graft loss | 1 | 2 |
| Infection | 12 | 17 |
| Death | 1 | 0 |
Direct and indirect cost related to treatment and management kidney transplant recipients
Results for this outcome have not been posted.
Collected over Adverse events are reported from the study start through Study Day 365.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| CYP3A5 Based Tacrolimus Dosing | 1/40 (2.5%) | 4/40 (10%) | 40/40 (100%) |
| Control | 0/57 (0%) | 2/57 (3.5%) | 57/57 (100%) |
| Event | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| Biopsy Proven Acute RejectionRenal and urinary disorders | 4/40 | 2/57 |
| Event | CYP3A5 Based Tacrolimus Dosing | Control |
|---|---|---|
| AnemiaBlood and lymphatic system disorders | 39/40 | 56/57 |
| HypomagnesemiaMetabolism and nutrition disorders | 33/40 | 53/57 |
| HyperkalemiaMetabolism and nutrition disorders | 28/40 | 44/57 |
| LeukopeniaBlood and lymphatic system disorders | 30/40 | 37/57 |
| Abnormal renal functionRenal and urinary disorders | 23/40 | 39/57 |
| Increase creatinineRenal and urinary disorders | 20/40 | 21/57 |
| HypophosphatemiaMetabolism and nutrition disorders | 20/40 | 27/57 |
| HyperglycemiaMetabolism and nutrition disorders | 18/40 | 23/57 |
| HypertensionCardiac disorders | 11/40 | 25/57 |
| TremorNervous system disorders | 10/40 | 22/57 |
| Age, Continuous(years) | CYP3A5 Based Tacrolimus Dosing | Control | Total |
|---|---|---|---|
| Median | 49 (18 to 64) | 51 (18 to 64) | 51 (18 to 64) |
| Sex: Female, Male(Participants) | CYP3A5 Based Tacrolimus Dosing | Control | Total |
|---|---|---|---|
| Female | 23 | 25 | 48 |
| Male | 17 | 32 | 49 |
| Race/Ethnicity, Customized(Participants) | CYP3A5 Based Tacrolimus Dosing | Control | Total |
|---|---|---|---|
| Black or African American | 21 | 31 | 52 |
| White | 14 | 21 | 35 |
| Asian | 2 | 3 | 5 |
| Hispanic | 2 | 2 | 4 |
| American Indian or Alaska Native | 1 | 0 | 1 |
| Region of Enrollment(Participants) | CYP3A5 Based Tacrolimus Dosing | Control | Total |
|---|---|---|---|
| United States | 40 | 57 | 97 |
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University of North Carolina, Chapel Hill