Evaluate the Efficacy and Safety of the ADVAGRAF®

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of 6-month treatment with Advagraf® converted from 12-month treatment with tacrolimus in stable liver transplant recipients. The secondary objective of this study is to evaluate severity of acute rejection confirmed by biopsy in 24 weeks, incidence of chronic rejection, patient and graft survival rates in 24 weeks, incidence of adverse events, blood pressure, tacrolimus trough level, drug compliance, and adherence.

Detailed Description
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This is single-center, single-group, open-label study, phase 4 IIT. The Subject is transplantated liver at a minimum of 12 month of screening and at least 12 month Treatment with a Tacrolimus stably And start screening after obtain consent to participate in clinical trials, if appropriate in the selection criteria do not apply to the exclusion criteria are enrolled in clinical trials. Administration method is following : The total daily dose of -1 tacrolimus will be converted to 1:1 (mg:mg) and the total daily dose of ADVAGRAF® will be administered only once daily in the morning for 24 weeks, starting from Day 0. Researchers must check the blood concentration of tacrolimus at each visit and adjust the dose to achieve the blood concentration maintaining at 5 10ng/ml of study treatment. Duration of treatment : The investigational product will be administered for 24 weeks. Tacrorimus blood level is 3-10 ng/ml for 6 months prior to screening and during the maintenance therapy. It is recommended to check the blood concentration of tacrolimus at each visit and adjust the dose to achieve the blood concentration maintaining at 5 10ng/ml of study treatment. (The lowest blood levels shall be adjusted at the discretion of the researchers, taking a blood sample is carried out in the morning before have of Investigational Product) Subjects, who participated in this clinical trial, are scheduled up to 5 times, and it will be proceed for 24 weeks. (screening and baseline, 3 weeks, 12 weeks, 24 weeks) admitted for 24 weeks including a screening visit.

Official Title
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A Phase IV, Single Center, Open-label, Single-arm Study to Evaluate the Efficacy and Safety of the Conversion to Tacrolimus Modified Release, ADVAGRAF® After 12 Month Treatment With a Tacrolimus Stably in Liver Transplant Recipients.

Conditions
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Evidence of Liver Transplantation

Intervention / Treatment
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* Drug: Advagraf


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 19 and 80 years old Those who were transplantated liver at a minimum of 12 month of screening and after 12 month Treatment with a Tacrolimus stably.(Brain dead transplantation or biological transplant no values) tacrolimus blood everage level is 3-10 ng/ml for at least 6 months prior to screening. Female subjects of child bearing potential must have a negative urine or serum pregnancy test prior to enrollment and at the end of study and must agree to practice effective birth control during the study. Subjects are stable clinically in the opinion of the investigator. Subjects capable of understanding the purpose and risks of the study, having been fully informed and has given written informed consent to participate in the study Exclusion Criteria: Subjects having previously received an organ transplant excluding liver transplant. Or Subjects receiving an auxiliary graft or in whom a bio-artificial liver(cell system) has been used. Acute rejection confirmed by histologic response or the patient had chronic rejection Subjects diagnosed new malignant tumor before the pre-screening within five years , with the exception of basalioma or squamous cell carcinoma or carcinoma in situ of the skin that has been treated successfully. Subjects allergic to tacrolimus or investigational product. Subjects are unstable clinically state in the opinion of the investigator. Subjects with any form of substance abuse, psychiatric disorder or condition which, in the opinion of the investigator, may complicate communication with the investigator. Subjects participating or having participated in another clinical trial and/or those taking or having taken an investigational / non-registered drug in the past 28 days. Subjects taking forbidden concomitant medications or within 28 days prior to enroll. Subjects who are pregnant or breast-feeding mother. Subjects unlikely to comply with the visits scheduled in the protocol. Subjects with renal dysfunction on the investigator's point of view or serum creatinine > 1.6mg/dL or GFR(MDRD)<30mL/min in the baseline. Hepatic dysfunction: rising more than double the normal range of SGPT/ALT and/or SGOT/AST and/or bilirubin, hepatic cirrhosis

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 80 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: Health Services Research
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tacrolimus<br>conversion to Advagraf | Drug: Advagraf<br>* Researchers must check the blood concentration of tacrolimus at each visit and adjust the dose to achieve the blood concentration maintaining at 5 10ng/ml of study treatment. Duration of treatment The investigational product will be administered for 24 weeks. (The lowest blood levels shall be adjusted at the discretion of the researchers, taking a blood sample is carried out in the morning before administrated of Investigational Product) Tacrolimus blood level is 3-10 ng/ml for 6 months prior to screening and during the maintenance therapy. ( ① -1day to enrollment : swich to the day before ADVAGRAF®, ② 0day to enrollment : the day swich to ADVAGRAF® ) Duration of treatment the investigational product will be administered for 24 weeks.<br>* Other names: tacrolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute rejection confirmed by biopsy in 24 weeks after conversion | Incidence of acute rejection (%) = no. of subjects who had acute rejection at least once / no. of all the subjects in the relevant analysis set * 100 Only acute rejection confirmed by biopsy will be recognized. In addition, concomitant immunosuppressants other than tacrolimus will be divided into sub-groups (by type and dosage/administration), and point estimation and calculation of 95% two-sided confidence interval will be conducted for incidence of acute rejection. | within 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of acute rejection confirmed by biopsy in 24 weeks after conversion | * For the subjects who developed acute rejection at least once, severity of acute rejection is defined as the highest severity. | within 24 weeks | 
| Incidence of chronic rejection | * Chronic rejection will be confirmed by biopsy. | within 24 weeks | 
| Patient and graft survival rates in 24 weeks after conversion |  | within 24 weeks | 
| Time from conversion to onset of acute rejection |  | within 24 weeks | 
| Tacrolimus trough level at each visit |  | within 24 weeks | 
| Incidence of adverse events |  | within 24 weeks | 
| Tacrolimus compliance | Evaluation of adherence through a subject questionnaire | within 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADVGRAF®, Liver transplantation, tacrolimus.