Liver Transplantation Clinical Trial
Official title:
Search for Transcriptional Biomarkers in a Conversion Protocol From Calcineurin Inhibitors to Mycophenolate Mofetil Monotherapy
As is well known, immunosuppressive treatment (IS) after liver transplantation has several and frequents adverse effects that limit the survival of the graft and recipients. Because of that, it is desirable that these recipients were able to receive a mild IS regime with a better safety profile. An attempt to get that aim has been evaluated in several trials in the past, and consist in to change the IS regime from an calcineurin inhibitors (CNI) based to another less intense and with less adverse effects based on mycophenolate mofetil (MMF), which is known to have a better safety profile. The success rate of this strategy(i.e. complete conversion in absence of rejection) has a wide range from 100% to 50% approximately. However it is accepted that this strategy is associated with the improvement of several adverse effects of CNIs such as renal failure and dyslipemia. This study's aim is to perform IS conversion from CNI to MMF monotherapy and look for transcriptional biomarkers employing a whole genome expression study performed with microarrays at baseline on liver tissue and/or PBMCs to try to find a differential gene expression able to correlate with a successful conversion and thus, to generate a set of transcriptional biomarkers potentially able to predict the result of the IS conversion on an independent cohort of liver recipients.
Introduction: Immunosuppressive treatment (IS) has several and frequents adverse effects;
among them are: severe infections, diabetes mellitus, arterial hypertension, osteoporosis,
neurologic disorders, renal failure, dyslipemias, increased cardiovascular risk, cancer,
etc. After 5 years, 18% of liver receptors develop renal failure, the risk of developing
cancer is three times higher after LT and 30% of liver graft receptors previously infected
by hepatitis C virus (HCV) have cirrhosis 5 years after LT, probably because of the effect
of IS on viral kinetics. An ideal situation would be that liver transplant recipients
receive enough IS to inhibit the immune response against the allograft, while avoiding an
excessive effect over the capacity of the immune system to recognize pathogens, tumoral
cells and minimizing the adverse effects or even more, the indefinite graft acceptance in
the complete absence of IS, concept that in clinic in called operational tolerance (OT). OT
occurs in around 20% of liver recipients. So although the potential benefit is important it
affects just a small fraction of liver recipients. A different but related strategy has been
evaluated in several trials in the past, and consist in to change from an IS based on
calcineurin inhibitors (CNI) to another less intense based on mofetil mycophenolate (MMF),
which is known to have less adverse effects, preserve renal function and do not affect the
function and proliferation of T regulatory cells, which are involved in the development of
OT. In a recent study (in press), the investigators performed an IS withdrawal to over a
hundred liver recipients and the investigators found that those who were classified as
operationally tolerant (40%) where those with a longer time elapsed since LT to IS
withdrawal, those who received lower doses of CNI and those who received MMF monotherapy.
The investigators were able also to discriminate between operationally tolerant liver
recipients and those who developed a rejection based on its differential gene expression
(evaluated by whole genome microarray) just before the ISwithdrawal.
Study's aim: to perform IS conversion from CNI to MMF monotherapy and look for
transcriptional biomarkers employing whole a genome expression study performed with
microarrays at baseline on liver tissue and PBMCs to try to find a set differentially
expressed genes able to correlate with a successful conversion and thus, to generate a set
of transcriptional biomarkers potentially able to predict the result of the IS conversion on
an independent cohort of liver recipients.
Methods: Forty patients will be recruited among our cohort of liver transplant recipients.
The study will last 48 weeks. Inclusion criteria will be a) liver transplantation more than
2 years ago, b) stable graft function, b) no history of autoimmune liver disease, c) absence
of rejection in the last 12 months, d) Use of calcineurin inhibitors (CNI) as monotherapy,
e)absence of rejection on baseline liver biopsy, d) tacrolimus trough levels > 3 ng/ml or
cyclosporine C2 levels > 30 ng/ml, e) signature of the informed consent form. After
screening procedure mycophenolate mofetil will be started (week -4) at a dose of 500 mg
twice a day for two weeks and then (week -2) increased to 1000 mg twice a day and CNI will
be reduced at the 50% of the initial dose. After two weeks (week 0) CNI will be completely
discontinued(complete IS conversion). The investigators will follow up patients every 4
weeks up to 48 weeks after the complete IS conversion. The complete study period will last
52 weeks. At baseline mRNA fron liver samples and peripheral blood mononuclear cells will be
isolated. This mRNA will be used to evaluate whole genome expression using Affimetrix
microarrays. Besides, T regulatory cells frequency will be measured using peripheral blood
cell immunophenotyping at baseline and at the end of the follow up. Clinical variables will
be evaluated to determined the evolution of renal function and other cardiovascular risk
factors.
Expected results: The investigators expect that at the end of the study most of the
recipients will have been able to have a successful rejection and a minor group (around 30%)
will not be able to do it because of rejection. Then baseline mRNA samples will be used to
perform whole genome microarrays. Using bioinformatics procedures the investigators will
make an attempt to establish a differential gene expression among those with a successful
conversion and those that develop rejection. This will allow the investigators to determine
the smallest set of genes able to discriminate between those patients. Gene expression will
be also correlated with peripheral blood cell immunophenotyping and clinical variables.
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Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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