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

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT03020589
• Collaborator: (none)
• Enrollment: 97
• Location: 1
• Arms: 2
• Actual Duration (Months): 64.7
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Feb 6, 2017
• Actual Primary Completion Date: Jul 31, 2021
• Actual Study Completion Date: Jun 28, 2022

Arms and Interventions

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 Names: 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.

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation [Day 3 after transplantation]

2. Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation [Day 7 after transplantation]

Secondary Outcome Measures

1. Incidence of Biopsy Proven Acute Rejection (BPAR) [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 [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 [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 [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 [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 [12 months]

   Direct and indirect cost related to treatment and management kidney transplant recipients

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univeristy of North Carolina	Chapel Hill	North Carolina	United States	27514

Sponsors and Collaborators

• University of North Carolina, Chapel Hill

Investigators

• Principal Investigator: Alexander Toledo, MD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 9, 2018

More Information

Publications

None provided.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT03020589
• Other Study ID Numbers: 16-2073
• First Posted: Jan 13, 2017
• Last Update Posted: Jul 21, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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: Tacrolimus

Study Results

Participant Flow

Arm/Group Title	CYP3A5 Based Tacrolimus Dosing	Control
Arm/Group Description	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. Tacrolimus: See description in arm/group sections	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.
Period Title: Overall Study
STARTED	40	57
COMPLETED	40	57
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	CYP3A5 Based Tacrolimus Dosing	Control	Total
Arm/Group Description	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. Tacrolimus: See description in arm/group sections	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.	Total of all reporting groups
Overall Participants	40	57	97
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	49	51	51
Sex: Female, Male (Count of Participants)
Female	23 57.5%	25 43.9%	48 49.5%
Male	17 42.5%	32 56.1%	49 50.5%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	21 52.5%	31 54.4%	52 53.6%
White	14 35%	21 36.8%	35 36.1%
Asian	2 5%	3 5.3%	5 5.2%
Hispanic	2 5%	2 3.5%	4 4.1%
American Indian or Alaska Native	1 2.5%	0 0%	1 1%
Region of Enrollment (Count of Participants)
United States	40 100%	57 100%	97 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CYP3A5 Based Tacrolimus Dosing	Control
Arm/Group Description	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. Tacrolimus: See description in arm/group sections	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.
Measure Participants	40	57
Number [proportion of participants]	0.2 0.5%	0.14 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CYP3A5 Based Tacrolimus Dosing, Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 95%; 0.67 to 2.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CYP3A5 Based Tacrolimus Dosing	Control
Arm/Group Description	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. Tacrolimus: See description in arm/group sections	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.
Measure Participants	40	57
Number [Proportion of participants]	0.29 0.7%	0.21 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CYP3A5 Based Tacrolimus Dosing, Control
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.72 to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Incidence of Biopsy Proven Acute Rejection (BPAR)
Description	The incidence of BPAR within the first 3 months, 3-6 months, 6-9 months, and 6-12 months after transplantation
Time Frame	3 months, 3-6 months, 6-9 months, and 6-12 months after transplantation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Tacrolimus Level
Description	Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL)
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Incidence of Acute and Chronic Renal Impairment
Description	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.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Incidence of Adverse Outcomes
Description	Incidence of adverse outcomes (ie, graft rejection, graft loss, renal impairment, adverse drug events, tacrolimus toxicities, and death)
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Direct and Indirect Costs
Description	Direct and indirect cost related to treatment and management kidney transplant recipients
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events are reported from the study start through Study Day 7.
Arm/Group Title	CYP3A5 Based Tacrolimus Dosing		Control
Arm/Group Description	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. Tacrolimus: See description in arm/group sections		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.
All Cause Mortality
	CYP3A5 Based Tacrolimus Dosing		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/40 (2.5%)		0/57 (0%)
Serious Adverse Events
	CYP3A5 Based Tacrolimus Dosing		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/57 (0%)
Other (Not Including Serious) Adverse Events
	CYP3A5 Based Tacrolimus Dosing		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/40 (100%)		57/57 (100%)
Blood and lymphatic system disorders
Leukopenia	6/40 (15%)	6	5/57 (8.8%)	5
Anemia	40/40 (100%)	40	29/57 (50.9%)	29
Cardiac disorders
Hypertension	19/40 (47.5%)	19	31/57 (54.4%)	31
Gastrointestinal disorders
Diarrhea	5/40 (12.5%)	5	8/57 (14%)	8
Nausea	16/40 (40%)	16	9/57 (15.8%)	9
Constipation	7/40 (17.5%)	7	7/57 (12.3%)	7
Vomiting	4/40 (10%)	4	4/57 (7%)	4
Infections and infestations
Infection	2/40 (5%)	2	1/57 (1.8%)	1
Metabolism and nutrition disorders
Hyperkalemia	21/40 (52.5%)	21	23/57 (40.4%)	23
Hyperglycemia	31/40 (77.5%)	31	17/57 (29.8%)	17
Hypomagnesemia	14/40 (35%)	14	25/57 (43.9%)	25
Hypophosphatemia	14/40 (35%)	14	15/57 (26.3%)	15
Hyperlipidemia	1/40 (2.5%)	1	0/57 (0%)	0
Edema	7/40 (17.5%)	7	8/57 (14%)	8
Hypokalemia	3/40 (7.5%)	3	5/57 (8.8%)	5
Nervous system disorders
Neurotoxicity	1/40 (2.5%)	1	1/57 (1.8%)	1
Tremor	3/40 (7.5%)	3	2/57 (3.5%)	2
Headache	3/40 (7.5%)	3	6/57 (10.5%)	6
Renal and urinary disorders
Abnormal renal function	36/40 (90%)	36	22/57 (38.6%)	22
Increase creatinine	14/40 (35%)	14	13/57 (22.8%)	13
Delayed Graft Function Requiring Dialysis	10/40 (25%)	10	2/57 (3.5%)	2
Acute rejection	0/40 (0%)	0	1/57 (1.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.