Trial Outcomes & Findings for Study of Pharmacogenomic-Guided Tacrolimus Dosing and Monitoring in Kidney Transplant Recipients (NCT NCT03020589)

NCT ID: NCT03020589

Last Updated: 2023-06-26

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

97 participants

Primary outcome timeframe

Day 3 after transplantation

Results posted on

2023-06-26

Participant Flow

Participant milestones

Participant milestones
Measure	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. Tacrolimus: See description in arm/group sections	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.
Overall Study STARTED	40	57
Overall Study COMPLETED	40	57
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CYP3A5 Based Tacrolimus Dosing n=40 Participants 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	Control n=57 Participants 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 n=97 Participants Total of all reporting groups
Age, Continuous	49 years n=99 Participants	51 years n=107 Participants	51 years n=206 Participants
Sex: Female, Male Female	23 Participants n=99 Participants	25 Participants n=107 Participants	48 Participants n=206 Participants
Sex: Female, Male Male	17 Participants n=99 Participants	32 Participants n=107 Participants	49 Participants n=206 Participants
Race/Ethnicity, Customized Black or African American	21 Participants n=99 Participants	31 Participants n=107 Participants	52 Participants n=206 Participants
Race/Ethnicity, Customized White	14 Participants n=99 Participants	21 Participants n=107 Participants	35 Participants n=206 Participants
Race/Ethnicity, Customized Asian	2 Participants n=99 Participants	3 Participants n=107 Participants	5 Participants n=206 Participants
Race/Ethnicity, Customized Hispanic	2 Participants n=99 Participants	2 Participants n=107 Participants	4 Participants n=206 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Region of Enrollment United States	40 Participants n=99 Participants	57 Participants n=107 Participants	97 Participants n=206 Participants

PRIMARY outcome

Timeframe: Day 3 after transplantation

Outcome measures

Outcome measures
Measure	CYP3A5 Based Tacrolimus Dosing n=40 Participants 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	Control n=57 Participants 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.
Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 3 After Kidney Transplantation	0.2 proportion of participants	0.14 proportion of participants

PRIMARY outcome

Timeframe: Day 7 after transplantation

Outcome measures

Outcome measures
Measure	CYP3A5 Based Tacrolimus Dosing n=40 Participants 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	Control n=57 Participants 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.
Proportion of Patients Reaching Target Tacrolimus Levels (8-10 ng/mL) on Day 7 After Kidney Transplantation	0.29 Proportion of participants	0.21 Proportion of participants

SECONDARY outcome

Timeframe: first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation

The number of events of BPAR within the first 3 months (Days 0 through 90), 91-180, and 181-365 days after transplantation

Outcome measures

Outcome measures
Measure	CYP3A5 Based Tacrolimus Dosing n=40 Participants 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	Control n=57 Participants 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.
Number of Events of Biopsy Proven Acute Rejection (BPAR) Days 0 through 90	3 BPAR events	2 BPAR events
Number of Events of Biopsy Proven Acute Rejection (BPAR) Days 91-180	3 BPAR events	0 BPAR events
Number of Events of Biopsy Proven Acute Rejection (BPAR) Days 181-365	0 BPAR events	0 BPAR events

SECONDARY outcome

Timeframe: 4 months

Time to achieve tacrolimus therapeutic range at 0 to 4 months (8-10 ng/mL)

Outcome measures

Outcome measures
Measure	CYP3A5 Based Tacrolimus Dosing n=40 Participants 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	Control n=57 Participants 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.
Tacrolimus Level	6.4 Days Standard Deviation 5.96	7.87 Days Standard Deviation 5.35

SECONDARY outcome

Timeframe: 12 months

Mean number of dose adjustments and/or drug alteration or addition due to insufficient immunosuppression.

Outcome measures

Outcome measures
Measure	CYP3A5 Based Tacrolimus Dosing n=40 Participants 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	Control n=57 Participants 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.
Mean Number of Dose Adjustments and/or Drug Alterations	7.86 Adjustments Standard Deviation 2.5	7.37 Adjustments Standard Deviation 2.7

SECONDARY outcome

Timeframe: 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/1.73m\^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).

Outcome measures

Outcome measures
Measure	CYP3A5 Based Tacrolimus Dosing n=40 Participants 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	Control n=57 Participants 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.
Percent of Participants With Chronic Renal Impairment by eGFR Category Mild : Week 1	23 percentage of participants	24 percentage of participants
Percent of Participants With Chronic Renal Impairment by eGFR Category Mild : Month12	53 percentage of participants	46 percentage of participants
Percent of Participants With Chronic Renal Impairment by eGFR Category Moderate : Week 1	35 percentage of participants	42 percentage of participants
Percent of Participants With Chronic Renal Impairment by eGFR Category Moderate : Month12	33 percentage of participants	51 percentage of participants
Percent of Participants With Chronic Renal Impairment by eGFR Category Severe : Week 1	43 percentage of participants	35 percentage of participants
Percent of Participants With Chronic Renal Impairment by eGFR Category Severe : Month12	13 percentage of participants	3 percentage of participants

SECONDARY outcome

Timeframe: 12 months

Number of adverse outcomes (i.e., graft loss, infection, and death)

Outcome measures

Outcome measures
Measure	CYP3A5 Based Tacrolimus Dosing n=40 Participants 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	Control n=57 Participants 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.
Number of Adverse Outcomes Graft loss	1 adverse outcomes	2 adverse outcomes
Number of Adverse Outcomes Infection	12 adverse outcomes	17 adverse outcomes
Number of Adverse Outcomes Death	1 adverse outcomes	0 adverse outcomes

OTHER_PRE_SPECIFIED outcome

Timeframe: 12 months

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

Outcome measures

Outcome data not reported

Adverse Events

CYP3A5 Based Tacrolimus Dosing

Serious events: 4 serious events

Other events: 40 other events

Deaths: 1 deaths

Control

Serious events: 2 serious events

Other events: 57 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	CYP3A5 Based Tacrolimus Dosing n=40 participants at risk 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	Control n=57 participants at risk 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.
Renal and urinary disorders Biopsy Proven Acute Rejection	10.0% 4/40 • Number of events 6 • Adverse events are reported from the study start through Study Day 365.	3.5% 2/57 • Number of events 2 • Adverse events are reported from the study start through Study Day 365.

Other adverse events

Additional Information

Robert Dupuis, PharmD

University of North Carolina at Chapel Hill

Phone: 919-966-6194

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	CYP3A5 Based Tacrolimus Dosing n=40 participants at risk 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	Control n=57 participants at risk 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.
Nervous system disorders Neurotoxicity	7.5% 3/40 • Number of events 5 • Adverse events are reported from the study start through Study Day 365.	8.8% 5/57 • Number of events 5 • Adverse events are reported from the study start through Study Day 365.
Nervous system disorders Tremor	25.0% 10/40 • Number of events 12 • Adverse events are reported from the study start through Study Day 365.	38.6% 22/57 • Number of events 25 • Adverse events are reported from the study start through Study Day 365.
Nervous system disorders Headache	27.5% 11/40 • Number of events 16 • Adverse events are reported from the study start through Study Day 365.	36.8% 21/57 • Number of events 26 • Adverse events are reported from the study start through Study Day 365.
Gastrointestinal disorders Diarrhea	30.0% 12/40 • Number of events 16 • Adverse events are reported from the study start through Study Day 365.	38.6% 22/57 • Number of events 37 • Adverse events are reported from the study start through Study Day 365.
Gastrointestinal disorders Nausea	30.0% 12/40 • Number of events 26 • Adverse events are reported from the study start through Study Day 365.	36.8% 21/57 • Number of events 28 • Adverse events are reported from the study start through Study Day 365.
Gastrointestinal disorders Constipation	22.5% 9/40 • Number of events 18 • Adverse events are reported from the study start through Study Day 365.	15.8% 9/57 • Number of events 12 • Adverse events are reported from the study start through Study Day 365.
Gastrointestinal disorders Vomiting	20.0% 8/40 • Number of events 14 • Adverse events are reported from the study start through Study Day 365.	17.5% 10/57 • Number of events 15 • Adverse events are reported from the study start through Study Day 365.
Cardiac disorders Hypertension	27.5% 11/40 • Number of events 24 • Adverse events are reported from the study start through Study Day 365.	43.9% 25/57 • Number of events 40 • Adverse events are reported from the study start through Study Day 365.
Renal and urinary disorders Abnormal renal function	57.5% 23/40 • Number of events 56 • Adverse events are reported from the study start through Study Day 365.	68.4% 39/57 • Number of events 73 • Adverse events are reported from the study start through Study Day 365.
Renal and urinary disorders Increase creatinine	50.0% 20/40 • Number of events 36 • Adverse events are reported from the study start through Study Day 365.	36.8% 21/57 • Number of events 29 • Adverse events are reported from the study start through Study Day 365.
Renal and urinary disorders Delayed Graft Function Requiring Dialysis	32.5% 13/40 • Number of events 13 • Adverse events are reported from the study start through Study Day 365.	21.1% 12/57 • Number of events 12 • Adverse events are reported from the study start through Study Day 365.
Blood and lymphatic system disorders Leukopenia	75.0% 30/40 • Number of events 86 • Adverse events are reported from the study start through Study Day 365.	64.9% 37/57 • Number of events 101 • Adverse events are reported from the study start through Study Day 365.
Blood and lymphatic system disorders Anemia	97.5% 39/40 • Number of events 115 • Adverse events are reported from the study start through Study Day 365.	98.2% 56/57 • Number of events 96 • Adverse events are reported from the study start through Study Day 365.
Metabolism and nutrition disorders Hyperkalemia	70.0% 28/40 • Number of events 65 • Adverse events are reported from the study start through Study Day 365.	77.2% 44/57 • Number of events 90 • Adverse events are reported from the study start through Study Day 365.
Metabolism and nutrition disorders Hyperglycemia	45.0% 18/40 • Number of events 89 • Adverse events are reported from the study start through Study Day 365.	40.4% 23/57 • Number of events 53 • Adverse events are reported from the study start through Study Day 365.
Metabolism and nutrition disorders Hypomagnesemia	82.5% 33/40 • Number of events 94 • Adverse events are reported from the study start through Study Day 365.	93.0% 53/57 • Number of events 145 • Adverse events are reported from the study start through Study Day 365.
Metabolism and nutrition disorders Hypophosphatemia	50.0% 20/40 • Number of events 34 • Adverse events are reported from the study start through Study Day 365.	47.4% 27/57 • Number of events 48 • Adverse events are reported from the study start through Study Day 365.
Metabolism and nutrition disorders Hyperlipidemia	17.5% 7/40 • Number of events 7 • Adverse events are reported from the study start through Study Day 365.	24.6% 14/57 • Number of events 16 • Adverse events are reported from the study start through Study Day 365.
Metabolism and nutrition disorders Edema	22.5% 9/40 • Number of events 20 • Adverse events are reported from the study start through Study Day 365.	21.1% 12/57 • Number of events 22 • Adverse events are reported from the study start through Study Day 365.
Infections and infestations Infection	25.0% 10/40 • Number of events 12 • Adverse events are reported from the study start through Study Day 365.	21.1% 12/57 • Number of events 17 • Adverse events are reported from the study start through Study Day 365.
Metabolism and nutrition disorders Hypokalemia	17.5% 7/40 • Number of events 9 • Adverse events are reported from the study start through Study Day 365.	14.0% 8/57 • Number of events 9 • Adverse events are reported from the study start through Study Day 365.
Renal and urinary disorders Graft loss	2.5% 1/40 • Number of events 1 • Adverse events are reported from the study start through Study Day 365.	3.5% 2/57 • Number of events 2 • Adverse events are reported from the study start through Study Day 365.