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Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients (TAC3A5)

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ClinicalTrials.gov Identifier: NCT03020589
Recruitment Status : Completed
First Posted : January 13, 2017
Results First Posted : July 21, 2022
Last Update Posted : July 21, 2022
Sponsor:
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

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.

Condition or disease Intervention/treatment Phase
Renal Transplant Drug: Tacrolimus Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 97 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients
Actual Study Start Date : February 6, 2017
Actual Primary Completion Date : July 31, 2021
Actual Study Completion Date : June 28, 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

Arm Intervention/treatment
Experimental: CYP3A5 based tacrolimus dosing
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
See description in arm/group sections
Other Name: Prograf, Advagraf

No Intervention: Control
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.



Primary Outcome Measures :
  1. Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation [ Time Frame: Day 3 after transplantation ]
  2. Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation [ Time Frame: Day 7 after transplantation ]

Secondary Outcome Measures :
  1. Incidence of Biopsy Proven Acute Rejection (BPAR) [ Time Frame: 3 months, 3-6 months, 6-9 months, and 6-12 months after transplantation ]
    The incidence of BPAR within the first 3 months, 3-6 months, 6-9 months, and 6-12 months after transplantation

  2. Tacrolimus Level [ Time Frame: 4 months ]
    Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL)

  3. Proportion of Patients Who Had Dose Adjustments and/or Drug Alterations [ Time Frame: 12 months ]
    Proportion of patients who had dose adjustments and/or drug alteration or addition due to insufficient immunosuppression

  4. Incidence of Acute and Chronic Renal Impairment [ Time Frame: 12 months ]
    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/1.73m2 to 89 mL/min/1.73m2), moderate (eGFR of 30 mL/min/1.73m2 to 59 mL/min/1.73m2), or severe renal impairment (eGFR <30 mL/min/1.73m2). Will be reported as a composite endpoint.

  5. Incidence of Adverse Outcomes [ Time Frame: 12 months ]
    Incidence of adverse outcomes (ie, graft rejection, graft loss, renal impairment, adverse drug events, tacrolimus toxicities, and death)


Other Outcome Measures:
  1. Direct and Indirect Costs [ Time Frame: 12 months ]
    Direct and indirect cost related to treatment and management kidney transplant recipients



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03020589


Locations
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United States, North Carolina
Univeristy of North Carolina
Chapel Hill, North Carolina, United States, 27514
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Investigators
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Principal Investigator: Alexander Toledo, MD University of North Carolina, Chapel Hill
  Study Documents (Full-Text)

Documents provided by University of North Carolina, Chapel Hill:
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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT03020589    
Other Study ID Numbers: 16-2073
First Posted: January 13, 2017    Key Record Dates
Results First Posted: July 21, 2022
Last Update Posted: July 21, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No participant data will be shared outside the research team.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of North Carolina, Chapel Hill:
Renal Transplant
Tacrolimus
UNC
Phase IV
Additional relevant MeSH terms:
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Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action