Efficacy and Safety Study of a 4-Month Post-Renal Transplant Dose Reduction of Tacrolimus(ADEQUATE) (ADEQUATE)

Efficacy and Safety Outcome of Two Different Targets of Advagraf® Trough Levels Between 4 Months and 12 Months After Transplantation Among de Novo Renal Transplant Recipients.

This prospective, interventional, open label, randomized, multicenter study was designed to determine the risk/benefit ratio of a 50 % reduction of Advagraf® daily dose, 4 months after transplantation. Randomized patients are to be stable with their tacrolimus daily dose required to reach targeted tacrolimus trough levels. Based on Month-3 eligibility assessments, patients will be randomized in two groups (1:1): patients with 50 % reduction of the daily dose of Advagraf® 4 months after transplantation, and patients kept on their usual dose. The benefit/risk ratio will include the assessment of renal function, histological lesions from both alloreactivity and CNI nephrotoxicity, and safety data (metabolic and infectious diseases).

Study Overview

• Status: Unknown
• Conditions: De Novo Transplant Disease
• Intervention / Treatment: Drug: Tacrolimus targeted half-dose; Drug: Tacrolimus targeted plain dose

• Study Type: Interventional
• Enrollment (Actual): 286
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • Hopital Sud
  • Angers, France
    • CHU de Angers
  • Bois-Guillaume, France, 76130
    • Hôpital Bois-Guillaume
  • Brest, France
    • Hôpital Cavale Blanche
  • Caen, France
    • CHU de Caen
  • Clermont-Ferrand, France
    • Hopital Gabriel Montpied
  • Le Kremlin Bicêtre, France
    • Hôpital Bicêtre
  • Limoges, France
    • Hôpital Dupuytren
  • Nice, France
    • Hôpital ARCHET II
  • Paris, France
    • Hôpital Necker
  • Paris, France, 75015
    • HEGP
  • Reims, France
    • Hôpital Maison Blanche
  • Rennes, France
    • Hôpital Pontchaillou
  • Strasbourg, France
    • Hopital Civil
  • Toulouse, France
    • CHU de Toulouse
  • Tours, France
    • CHRU de Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age between 18 et 70 years
• Patient accepting to give a written informed consent
• Recipients of a first renal allograft
• Cadaver or living transplantation or living (non HLA identical) donor with compatible ABO blood type.
• Absence of positive DSA using Luminex®, MFI>1,000
• Negative cross-match in cytotoxicity
• Patient without difficulty to understand and communicate with the investigator and his collaborators
• Patient entitled to Health System benefits or other such benefits.

Exclusion Criteria:

• Multiple organ transplantation
• Recipients of a dual kidney transplant
• Previous renal allograft
• History of any other transplantation
• Receiving a graft from a non-heart-beating donor
• Patient BMI > 35
• Patients with evidence of severe liver disease, including abnormal liver profile (AST, ALT, or total bilirubin > 3 times upper limit of normal) at screening.
• Significant severe infection, active peptic ulcer and/or difficulty to absorb oral drugs (active upper gastro-intestinal tract malabsorption syndrome)
• HIV-positive patients, or with an active B or C hepatitis
• Patients with de novo malignancy prior to transplantation, other than efficiently treated basal or squamous cell carcinoma of the skin.
• Leucocyte count lower than 2500/mm3
• Female patients who are pregnant, lactating or of child bearing potential and not practicing an approved method of birth control.
• Known allergy or intolerance to basiliximab, tacrolimus, macrolide antibiotics, corticosteroids, or mycophenolate mofetil or any of the product excipients
• Participation in a clinical trial or expanded access trial with an investigational drug within 4 weeks prior to enrollment or concomitantly with this study
• Any clinical condition which, in the opinion of the investigator, would not allow safe completion of the study

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: Group A - tacrolimus half-dose; Immunosuppressive strategy with 50 % reduction of Advagraf® daily dose at M4 (randomization) and unchanged MMF dose. Targeted tacrolimus trough level are to be higher than 3 ng/mL . If the dose is not in adequation with the dispensable units, the prescribed dose will be the closest higher dose. Drug: Tacrolimus targeted half-dose	Drug: Tacrolimus targeted half-dose; Other Names: Advagraf®
Experimental: Group B - tacrolimus unchanged dose; Immunosuppressive strategy will remain identical after randomization (M4): unchanged Advagraf® and MMF doses. Targeted tacrolimus trough level are to be between 7 and 12 ng/mL Drug: Tacrolimus targeted plain dose	Drug: Tacrolimus targeted plain dose; Other Names: Advagraf®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal function at one year post transplantation	Renal function at one year post transplantation estimated by the glomerular filtration rate (GFR) using MDRD 4 (Modification Diet in Renal Disease). Crude difference in renal function at one year between groups and the change of renal function between 4 months and one year in each group will be analyzed and compared.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine and compare according to randomized group	Routine graft histology at M12 assessed using Banff 2009 classification, with specific analysis of interstitial fibrosis (IF) using numeric quantification	12 months
To determine and compare according to randomized group	Glucose metabolism at M4 and M12	12 months
To determine and compare according to randomized group	Infection rate including BKV and CMV at M4 and M12	12 months
To determine and compare according to randomized group	Presence and intensity of Donor Specific Antibody (DSA) at M3 and M12	12 months
To determine and compare according to randomized group	Incidence of biopsy proven acute rejection episode at M12	12 months
To determine and compare according to randomized group	Graft and patient survival at M12	12 months
To determine and compare according to randomized group	Overall safety assessment	12 months

Collaborators and Investigators

• Sponsor: University Hospital, Tours
• Collaborators: Astellas Pharma Inc
• Investigators: Principal Investigator: Yvon LEBRANCHU, University Hospital, Tours

Publications and helpful links

General Publications

• Gatault P, Kamar N, Buchler M, Colosio C, Bertrand D, Durrbach A, Albano L, Rivalan J, Le Meur Y, Essig M, Bouvier N, Legendre C, Moulin B, Heng AE, Weestel PF, Sayegh J, Charpentier B, Rostaing L, Thervet E, Lebranchu Y. Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study. Am J Transplant. 2017 May;17(5):1370-1379. doi: 10.1111/ajt.14109. Epub 2017 Jan 3.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Anticipated): March 1, 2015
• Study Completion (Anticipated): March 1, 2015

Study Registration Dates

• First Submitted: June 11, 2012
• First Submitted That Met QC Criteria: December 5, 2012
• First Posted (Estimate): December 6, 2012

Study Record Updates

• Last Update Posted (Estimate): April 8, 2014
• Last Update Submitted That Met QC Criteria: April 7, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Tacrolimus; Transplantation; Renal
• 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: PHAO2011/YL/ADEQUATE; 2011-003184-29 (EudraCT Number)