Dosing Strategies for de Novo Once-daily Extended Release Tacrolimus (LCPT) in Kidney Transplant Recipients

Study Overview
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Brief Summary
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Outcomes after kidney transplantation have been significantly enhanced with the advances made in immunosuppressive therapies. Tacrolimus is currently marketed as an extended-release once-daily formulation dosing option for patients, decreasing pill burden and possibly decreasing adverse effects. Some transplant recipients have been shown to have higher dosage requirements. According to the literature, this can be linked to genetic disparities in the metabolism of tacrolimus.. This potential complication, where differences on specific genes alters metabolism of tacrolimus, can increase difficulty in getting to a therapeutic drug level for immunosuppresants and is one large factor that contributes to the fact that kidney transplant survival rates differ between patients. Due to the enhanced bioavailability of Meltdose formulation once-daily extended-release tacrolimus, its de novo use in recent research and practice has been shown to expedite achievement of target tacrolimus trough concentrations. De novo use of once-daily tacrolimus formulations is understudied. Through a prospective investigational study, we aim to determine the optimal strategy for de novo dosing of once-daily extended release tacrolimus (MeltDose formulation) for kidney transplant recipients at Temple University Hospital.

Detailed Description
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Patients will be identified when an organ from live or deceased donor becomes available for kidney transplant. Prior to receiving their kidney transplant, subjects will be screened for inclusion/exclusion criteria on the day of transplantation. During the pre-operative preparation for transplant, patients will be consented for surgery and consented for the study at the same time if they volunteer to be included. The transplant surgeon performing the transplant operation will be responsible for screening the patients for inclusion and exclusion criteria as well as obtaining informed consent. Patients will need to provide informed consent to be included in the study, and will receive a copy of their consent. Each potential participant will be approached by the transplant surgeon and informed of all information pertinent to the study prior to providing consent. No advertisements for recruitment will be performed and no compensation will be provided for participation. This study is a single center prospective observational study conducted at Temple University Hospital (TUH). All participants will be consented for all procedures involved in this study. This study will utilize the QUEST questionnaire (attached) to evaluate the severity of tremors at 1 month. Data to be collected includes tacrolimus trough levels, study drug dosing, hemoglobin A1c, incidence and severity of tremors, potassium, glomerular filtration rate, and rejection episodes. Day 0 Study drug (tacrolimus) initiated at 0.13/mg/kg/day for all patients (the day of initiation decided per transplant surgeon discretion) Day 0-4 Inpatient laboratory parameters checked every 24 hours (serum creatinine, tacrolimus level, glomerular filtration rate, potassium, blood glucose) Day 4-30 Outpatient laboratory parameters checked three times weekly on Monday, Wednesday, and Friday (serum creatinine, tacrolimus level, glomerular filtration rate, potassium, blood glucose) Day 30 visit (within 5 days) Draw tacrolimus trough levels, serum creatinine, estimated glomerular filtration rate, serum potassium, and blood glucose. Complete tremor questionnaire with participant. During or prior to Day 30 visit Oral swab performed to be analyzed for testing of metabolic enzymatic activity (This will be performed to determine ability of the patient to metabolize tacrolimus)

Official Title
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Dosing Strategies for de Novo Once-daily Extended Release Tacrolimus (LCPT) in Kidney Transplant Recipients

Conditions
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Kidney Transplant

Intervention / Treatment
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* Drug: Tacrolimus Extended Release Oral Tablet [Envarsus] 0.13mg/kg/day initiated within post-operative day 3 after kidney transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient who is 18 years of age or older receiving a kidney transplant at the Temple University Hospital's Kidney Transplant Program who are capable of understanding consent and volunteer to take part in the study Exclusion Criteria: Scheduled for multiple organ transplant at enrollment Non-English speaking Pregnant women Moderate-severe hepatic impairment (Child Pugh > 10 or bilirubin > 2) Existing contraindications to tacrolimus-based products including known hypersensitivity to tacrolimus or any other component of the formulation Receiving concomitant medications known to have strong drug-drug interaction potential with tacrolimus including fluconazole, voriconazole, posaconazole, isavuconazole, itraconazole, ketoconazole, diltiazem, verapamil, metronidazole, erythromycin, clarithromycin, rifampin, rifabutin, rifapentine, phenytoin, fosphenytoin, phenobarbital, primidone, carbamazepine, St. John's Wort, efavirenz, neivrapine, etravirine, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, cobicistat

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus extended-release 0.13mg/kg/day<br>Tacrolimus extended-release is initiated within post-operative day 3 of kidney transplant | Drug: Tacrolimus Extended Release Oral Tablet [Envarsus] 0.13mg/kg/day initiated within post-operative day 3 after kidney transplant<br>* Study drug (tacrolimus extended-release) initiated at 0.13/mg/kg/day for all patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Therapeutic Tacrolimus Trough Concentration From Initiation of Tacrolimus Extended Release Measured in Days | Therapeutic tacrolimus trough= 8-10ng/mL | Within the first 30 days of kidney transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Estimated Glomerular Filtration Rate Within 30 Days | eGFR | 30 days | 
| Number of Participants With no Impact of Tremor on Quality of Life | Assessed via QUEST questionnaire which includes a self-assessment of tremor impact on quality of life. The following areas related to impact on tremor are assessed by this scale: Patients will select the severity of tremor in each of the following body parts on a scale of (none: no tremor at any time, mild: mild tremor not causing difficulty in performing any activities, moderate: tremor causes difficulty in performing some activities, marked: tremor causes difficulty in performing most or all activities, severe: tremor prevents performing some activities). Head Voice Right arm/hand Left arm/hand Right leg/foot Left leg/foot Several questions will be answered relating to specific situations and the impact of tremor on those situations (scale: never/no, rarely, sometimes, frequently, always/yes, not applicable) | At 30 days after kidney transplant | 
| Weight-based Tacrolimus Dose During Study Period | Weight-based tacrolimus dose during study period | 30 days | 
| Tacrolimus Dose During Study Period | Tacrolimus dose during study period | 30 days | 
| Tacrolimus Trough Level During Study Period | Tacrolimus trough level during study period | 30 days | 
| Weight Based Tacrolimus Dose at Therapeutic Concentration | Weight based tacrolimus dose at therapeutic concentration | At time of therapeutic tacrolimus concentration up to 30 days | 
| Tacrolimus Dose at Therapeutic Tacrolimus Concentration | Tacrolimus dose at therapeutic tacrolimus concentration | At time of therapeutic tacrolimus concentration up to 30 days |