Conversion Prograf® to Advagraf® at D7 Versus D90 After Liver Transplantation

Study Overview
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Brief Summary
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The best period for the conversion from Prograf (tacrolimus administered twice daily) to Advagraf (once-daily prolonged-release tacrolimus) remains unknown. The aim of this prospective, randomized, multicenter trial is to prove the non-inferiority of the early conversion (at D7) versus the conversion at D90 after liver transplantation. The primary objective will be to evaluate the incidence of a first biopsy-proven acute rejection in the 6 first months, and prove the non-inferiority of the conversion at D7 + / - 3 versus the conversion at D90 + / - 5 (reference group). If non-inferiority is proved, the two strategies will be compared in terms of superiority. 250 patients will be included. Three ancillary studies will be added : a PK study in a subgroup of 40 patients (20 patients per arm), an assay of the calcineurin activity on a subgroup of 40 patients, and a medicoeconomic study in all patients

Detailed Description
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Rationale : Conversion from Prograf (tacrolimus administered twice daily) to Advagraf (once-daily prolonged-release tacrolimus) is currently proposed in both stable and de novo liver transplant recipients. However, the early conversion (around D7 after transplantation), during hospitalization, may be difficult due to the more frequent need of dose adjustments under Advagraf than under Prograf, so that there is no consensus on the best period for the conversion. The aim of this prospective, randomized, multicenter trial is to prove the non-inferiority - in terms of efficacy - of the early conversion (at D7) versus the conversion at D90 after liver transplantation. Primary objective : To evaluate the incidence of biopsy-proven acute rejection in the 6 first months after liver transplantation, and prove the non-inferiority of the conversion at D7 + / - 3 versus the conversion at D90 + / - 5 (reference group). Secondary objectives : Compare the two strategies in terms of: Severity of acute rejection (criteres of Banff 97) Steroid-resistant acute rejection Number of dose adjustments to obtain the target trough level after conversion Patient and graft survival Analyse the PK profile of two subgroups (20 patients in each arm) under Advagraf Measure the calcineurin activity in the two groups (in the patients selected for the PK analysis) Evaluate tolerance, with a particular focus on the renal function at 6 months (glomerular filtration rate using MDRD4) and on adverse events. Primary endpoint: Percentage of patients with a first episode of biopsy-proven acute rejection. Methodology : Multicenter (13 French liver transplant centers), randomized (central randomisation), open study, of non-inferiority, comparing the efficacy at 6 months of two strategies of conversion from Prograf to Advagraf (D7 + / - 3 versus D90 + / - 5), in addition to mycophenolate mofetil and steroids, in liver transplant recipients. If non-inferiority is proved, the two strategies will be compared in terms of superiority. Inclusion of 250 patients (to analyse at least 112 patients in each arm). Calculation of the sample size is based on the following data: Incidence of acute rejection at 6 months = 20% in the 2 groups, Non-inferiority margin = 15%, alpha risk = 2.5%, power = 80%). Treatments : Prograf introduced at 0,1 - 0,2 mg/kg/day Mycophenolate mofetil : 1g TD Steroids according to the current use in each center Trough blood concentration of tacrolimus will be 8 - 15 ng/mL during the first 3 months, then 5 à 12 ng/mL thereafter. PK study: For the 40 patients included in the PK study (20 patients per arm), the PK profile (C0, Cmax and AUC) will be established on 9 points : 0 (before Advagraf administration) then at 20min, 40 min, 60 min, 2h, 3h, 4h, 6h, 8h. 7 days after conversion in the first group (early conversion) 14 + / - 5 days after conversion in the other group (conversion at D90) Calcineurin activity will be assayed on the blood samples used for the trough concentration determination at D5, D7, M1, M3 and M6 and on a baseline sample. Medicoeconomic study : The costs induced by liver transplantation will be calculated in all the patients included and randomized according to the French recommendations.

Official Title
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Non-inferiority and Tolerance of Conversion From Prograf® to Advagraf® at D7 Versus D90 After Liver Transplantation

Conditions
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Immunosuppression After Liver Transplantation

Intervention / Treatment
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* Drug: Conversion at day 7 ± 3 Prograf® to Advagraf®
* Drug: Conversion at day 90±5 Prograf® to Advagraf®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : 18 to 75 years First liver transplantation No contra-indication to tacrolimus, mycophenolate mofetil or steroids Informed consent signed French Health Assurance Exclusion Criteria : Combined transplantation Severe uncontrolled infection Hypersensitivity to tacrolimus or its excipients, to other macrolides, to mycophenolate mofetil or its excipients Pregnant or lactating woman, or women of childbearing potential without adequate method of contraception Cancer or pasthistory of cancer other than basal or squamous cell carcinoma or hepatocellular carcinoma suitable for liver transplantation Patients with renal impairment where GFR is less than 30ml/min HIV positivity

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conversion at day 7 ± 3<br>Conversion from Prograf to Advagraf at D7 ± 3 | Drug: Conversion at day 7 ± 3 Prograf® to Advagraf®<br>* Conversion from Prograf® (tacrolimus administered twice daily) to Advagraf® (once-daily prolonged-release tacrolimus) at day 7±3<br>|
| Active Comparator: Conversion at day 90±5<br>Conversion from Prograf to Advagraf at 90±5 | Drug: Conversion at day 90±5 Prograf® to Advagraf®<br>* Conversion from Prograf® (tacrolimus administered twice daily) to Advagraf® (once-daily prolonged-release tacrolimus) at day 90±5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First episode of acute rejection during the first 6 months | First episode of acute rejection during the first 6 months | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal function | Glomerular filtration rate using MDRD4 | 6 months | 
| Adverse effects | All side effects | 6 months | 
| Severity of acute rejection | Histological severity of acute rejection using the Banff 2007 criteria | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver transplantation,, Conversion (Prograf® to Advagraf®),, Advagraf® ,, acute rejection,, GFR, Prograf® ,