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

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

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

Study Overview

• Status: Completed
• Conditions: Immunosuppression After Liver Transplantation
• Intervention / Treatment: Drug: Conversion at day 7 ± 3 Prograf® to Advagraf®; Drug: Conversion at day 90±5 Prograf® to Advagraf®

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Hôpital Pitié Salpêtrière unité médicale de transplantion hépatique

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Yvon Calmus, MD, PhD, Assistance Publique

Publications and helpful links

General Publications

• Allard M, Puszkiel A, Conti F, Chevillard L, Kamar N, Noe G, White-Koning M, Thomas-Schoemann A, Simon T, Vidal M, Calmus Y, Blanchet B. Pharmacokinetics and Pharmacodynamics of Once-daily Prolonged-release Tacrolimus in Liver Transplant Recipients. Clin Ther. 2019 May;41(5):882-896.e3. doi: 10.1016/j.clinthera.2019.03.006. Epub 2019 Apr 17.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2014
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): October 17, 2016

Study Registration Dates

• First Submitted: April 2, 2014
• First Submitted That Met QC Criteria: April 4, 2014
• First Posted (Estimate): April 7, 2014

Study Record Updates

• Last Update Posted (Actual): December 8, 2017
• Last Update Submitted That Met QC Criteria: December 7, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: GFR; Liver transplantation,; Conversion (Prograf® to Advagraf®),; Prograf® ,; Advagraf® ,; acute rejection,
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: P 120907; HAO 2012 (Other Identifier: University Hospital of Toulouse)