Bayesian Dose Adjustment of Immunosuppressants After Lung Transplantation (BASALT)

Evaluation of the Interest of Therapeutic Drug Monitoring of Immunosuppressants (Tacrolimus, Mycophenolate Mofetil) Based on Bayesian Estimation During the Three First Years Following Lung Transplantation, in Patients With or Without Cystic Fibrosis

The purpose of this study is to evaluate in lung or heart-lung transplant patients on tacrolimus and mycophenolate the impact of optimized mofetil (MMF) therapeutic drug monitoring and dose adjustment of both drugs on the incidence of treatment failure over the first three years post-transplantation.

Study Overview

• Status: Terminated
• Conditions: Lung and Heart-lung Transplantation
• Intervention / Treatment: Drug: Tacrolimus and MMF

Detailed Description

This research will be based on a prospective randomized trial comparing optimized TDM of tacrolimus and MMF to the current strategy of tacrolimus and MMF dose adjustment in lung transplant recipients. The study will focus on the first three years post-transplantation, as treatment failures (including BOS) occur mainly during this post-transplantation period. As the aim of tacrolimus and MMF dose individualization is to avoid over- or underexposure, for the purpose of this study treatment failure will be a composite criterion gathering events which reflect both over- and underexposure to tacrolimus and MMF.

Optimized TDM of tacrolimus and MMF based on blood tacrolimus and plasma MPA AUC Bayesian estimation will be compared to current strategies: tacrolimus dose adjustment based on trough levels (C0) and administration of a standard dose of MMF, decreased by the pulmonologist in case of adverse drug reactions or increased in case of inefficacy. The efficacy of optimized strategy vs. current strategies will be mainly evaluated through the incidence of treatment failure.

• Study Type: Interventional
• Enrollment (Anticipated): 180
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium
    • Service de Pneumologie
• France
  • Grenoble, France
    • Pôle Médecine Aiguë et Communautaire, Clinique de Pneumologie,
  • Lyon, France
    • Service de Pneumologie, HCL Lyon
  • Marseille, France
    • ApHm -Chirurgie thoracique
  • Nantes, France
    • Service de Pneumologie-CHU de Nantes
  • Paris, France
    • Service de Chirurgie Cardiovasculaire - Hôpital Georges Pompidou
  • Paris, France
    • Service de Pneumologie - CH de Suresnes
  • Paris, France
    • Service de Pneumologie - Phtisiologie - Hôpital Bichat
  • Strasbourg, France
    • Service de Pneumologie - CHU de Strasbourg

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

• Male and female patients aged 18 years or more
• CF and non-CF patients receiving single-lung or double-lung or heart-lung transplantation for the first time
• Patients on oral tacrolimus and MMF for at least 48 hours at the time of inclusion (administration via a naso-gastric tube possible if necessary)
• Patients without progressive chronic pathology jeopardizing short term patient and graft survival
• Patients accepting to comply with at least the evaluation visits planned in the investigation center over the first three years post-transplantation (D7, D14, M1, M3, M6, M12, M18, M24, M30, M36)
• Patients giving their free and informed written consent to participate in this study
• Patients with a health insurance policy or registered under a health insurance program

Exclusion Criteria:

• Patients aged less than 18 years or patients over 18 years under guardianship
• Patients who disagree with this research
• Patients with a contra-indication to receiving tacrolimus or MMF
• Patients on cyclosporine, sirolimus or everolimus
• Patients who have already benefited from a solid organ transplantation in the past (including lung or heart-lung transplantation)
• Patients infected by Burkholderia cenocepacia (Burkholderia cepacia genomovar III)
• Patients receiving HIV protease inhibitors (major pharmacokinetic interaction with tacrolimus)
• Pregnant or breastfeeding women or those of child-bearing age who do not use an efficient contraceptive method
• Drug users or patients suffering from neuro-psychiatric disorders preventing them from both proper comprehension of the protocol and reliable consent
• Patients already participating in another interventional clinical trial

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: 1; Optimized TDM of tacrolimus and MMF dosing	Drug: Tacrolimus and MMF; Tacrolimus: daily oral dose divided into 2 doses (morning and evening). MMF: daily dose divided into 2 doses at 12 hour intervals or 3 doses at 8 hour intervals.
Active Comparator: 2; Current tacrolimus and MMF dosing strategies	Drug: Tacrolimus and MMF; Tacrolimus: daily oral dose divided into 2 doses (morning and evening). MMF: daily dose divided into 2 doses at 12 hour intervals or 3 doses at 8 hour intervals.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Immunosuppressive treatment failure	Day 7, day 14, day 21; months 3, 6 and every six months afterwards up to 3 years posttransplantation

Secondary Outcome Measures

Outcome Measure	Time Frame
Efficacy score	Day 7, day 14, day 21; months 3, 6 and every six months afterwards up to 3 years posttransplantation
Toxicity score	Day 7, day 14, day 21; months 3, 6 and every six months afterwards up to 3 years posttransplantation
Benefit/risk ratio	Day 7, day 14, day 21; months 3, 6 and every six months afterwards up to 3 years posttransplantation
Each event composing the composite criterion	Day 7, day 14, day 21; months 3, 6 and every six months afterwards up to 3 years posttransplantation
Overall cost of patients monitoring	Day 7, day 14, day 21; months 3, 6 and every six months afterwards up to 3 years posttransplantation
Pharmacogenetic and proteomic analysis	Day 7, day 14, day 21; months 3, 6 and every six months afterwards up to 3 years posttransplantation

Collaborators and Investigators

• Sponsor: University Hospital, Limoges
• Investigators: Study Director: Pierre MARQUET, MD, CHU Limoges

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: September 10, 2009
• First Submitted That Met QC Criteria: September 10, 2009
• First Posted (Estimate): September 11, 2009

Study Record Updates

• Last Update Posted (Estimate): April 26, 2011
• Last Update Submitted That Met QC Criteria: April 23, 2011
• Last Verified: April 1, 2011

More Information

Terms related to this study

• Keywords: pharmacokinetics; immunosuppressant; Lung transplantation; tacrolimus; heart-lung transplantation; therapeutic drug monitoring; mycophenolate
• 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: I07038