Twice-daily Tacrolimus and Everolimus Convert to Once-daily Tacrolimus and Everolimus in Liver Transplant Recipient

A Six-month, Prospective, Single-center, Pilot Study Determining the Pharmacokinetics and Effectiveness of Twice-daily Tacolimus and Everolimus Regimen Convert to Once-daily Tacrolimus and Everolimus Regimen in Liver Transplant Patients

It has been identified that nonadherence to immunosuppressant regimen may cause long-term graft failure and death in solid organ transplant recipients. Therefore, simplification of the immunosuppression regimen by reducing daily dosing frequency may improve long-term outcome. The investigators will examine pharmacokinetics and safety profiles of stable liver transplant recipients receiving twice-daily TAC with EVR (BID) regimen and then being converted to once-daily TAC with EVR (QD) regimen over a 6-month study period post-conversion.

Study Overview

• Status: Completed
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: Tacrolimus and Everolimus

Detailed Description

Randomized trial of everolimus (EVR) with reduced tacrolimus (TAC) regimen after liver transplantation has shown similar incidence of composite efficacy failure rate to a standard tacrolimus regimen, but with superior renal function for up to three years. Recent studies have demonstrated comparable efficacy and safety profiles in liver transplant recipients receiving tacrolimus once-daily (QD) and tacrolimus twice-daily (BID) regimens. In kidney transplantation, once daily everolimus (QD) regimen has shown its safety and effectiveness. It has been identified that nonadherence to immunosuppressant regimen may cause long-term graft failure and death in solid organ transplant recipients. Therefore, simplification of the immunosuppression regimen (e.g. TAC with EVR) by reducing daily dosing frequency may improve long-term outcome. However, little is known about the effectiveness and safety of combined TAC and EVR once-daily (QD) regimen in liver transplant recipients. The investigator will examine pharmacokinetics and safety profiles of stable liver transplant recipients receiving twice-daily TAC with EVR (BID) regimen and then being converted to once-daily TAC with EVR (QD) regimen over a 6-month study period post-conversion.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• Taiwan
  • Taoyuan, Taiwan
    • Chang Gung Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key inclusion criteria

Stable liver transplant recipients are eligible for inclusion in this study and have to fulfill all of the following criteria:

1. Liver Transplant Recipients have received liver transplantations for at least 6+1 months prior to enrollment
2. Liver Transplant Recipients have no acute rejection episodes within 3 months prior to the enrollment and are clinically stable
3. Liver Transplant Recipients have been treated with twice-daily regimen of tacrolimus(TAC) plus everolimus(EVR) and TAC and EVR trough levels have stayed within targeted ranges for at least 6 weeks prior to enrollment
4. Provide written informed consent prior to inclusion.
5. Liver transplant recipients who are 18-65 years of age of a primary liver transplant
6. Allograft functioning at an acceptable level as defined by the AST, ALT, Total Bilirubin levels ≤3 times ULN prior to enrollment.
7. Abbreviated MDRD eGFR ≥ 30 mL/min/1.73m2. Key exclusion criteria

Patients fulfilling any of the following criteria are not eligible for inclusion in this study:

1. Patients who are recipients of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant. Patients who have a combined liver-kidney transplant.
2. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
3. Existence of any surgical, medical or mental conditions, other than the current transplantation, which, in the opinion of the investigator, might interfere with the objectives of the study.
4. Pregnant or nursing (lactating) women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tacrolimus and Everolimus BID; TAC BID (C0 2.5-5 ng/mL) EVR BID (1.0 mg BID targeted to C0 3-8 ng/mL) Other Names: Prograf; Advagraf; Zortress; Certican	Drug: Tacrolimus and Everolimus; In the TAC and EVR BID arm, everolimus will be initiated at a dose of 1.0 mg BID within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.15 mg/kg BID and then taper to 0.10 mg/kg BID to maintain trough (C0) concentration in the range 2.5-5 ng/mL. In the TAC and EVR QD arm, everolimus will be initiated at a dose of 2.0 mg QD within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.1-0.2 mg/kg/day QD to maintain trough (C0) concentration in the range 2.5-5 ng/mL.; Other Names: Prograf; Certican; Zortress; Advagraf
Experimental: Tacrolimus and Everolimus QD; TAC QD (C0 2.5-5 ng/mL) EVR QD (2.0 mg QD targeted to C0 3-8 ng/mL) Other Names: Prograf; Advagraf; Zortress; Certican	Drug: Tacrolimus and Everolimus; In the TAC and EVR BID arm, everolimus will be initiated at a dose of 1.0 mg BID within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.15 mg/kg BID and then taper to 0.10 mg/kg BID to maintain trough (C0) concentration in the range 2.5-5 ng/mL. In the TAC and EVR QD arm, everolimus will be initiated at a dose of 2.0 mg QD within 24 h of randomization with the dose adjusted from day 5 onward to maintain trough (C0) concentration in the range 3-8 ng/mL. Tacrolimus will be initiated at a dose of 0.1-0.2 mg/kg/day QD to maintain trough (C0) concentration in the range 2.5-5 ng/mL.; Other Names: Prograf; Certican; Zortress; Advagraf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate pharmacokinetic profile of everolimus and tacrolimus in liver transplant recipients on AUC (area under the curve)	Area under the plasma concentration versus time curve (AUC)	6 month

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital
• Investigators: Principal Investigator: WeiChen Lee, MD, Chang Gung Memorial Hospital

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): June 30, 2019
• Study Completion (Actual): May 30, 2020

Study Registration Dates

• First Submitted: February 1, 2016
• First Submitted That Met QC Criteria: August 21, 2017
• First Posted (Actual): August 22, 2017

Study Record Updates

• Last Update Posted (Actual): June 5, 2020
• Last Update Submitted That Met QC Criteria: June 4, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus; Everolimus
• Other Study ID Numbers: CRAD001HTW02T

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided