Status unknownNCT01034345Updated Dec 17, 2009

Effect of Rapamycin on Tolerance-related Biomarkers on Stable Liver Transplant Recipients

A Phase 2 interventional study of Sirolimus and Calcineurin inhibitor in Liver Transplantation, sponsored by Hospital Clinic of Barcelona. Status unknown at 1 site in Spain. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2009-12-17.

Sponsored by Hospital Clinic of Barcelona · Phase 2, Interventional, and Treatment

The sponsor has not verified this record recently (last verified Nov 2009), so the status shown — last known as Recruiting — may be out of date.

Phase: Phase 2
Study type: Interventional
Enrollment: 52
Allocation: Randomized
Ages: 18 Years to 75 Years
Sex: All

Study summary

In contrast to calcineurin inhibitors, sirolimus is known to exert remarkable tolerance-promoting properties in multiple animal transplant models. Whether sirolimus is capable of enhancing tolerance-related pathways and/or promoting complete withdrawal of immunosuppressive drugs in human transplant recipients has not been previously addressed. The goal of the investigators study is to evaluate the effects of sirolimus on previously identified tolerogenic pathways in humans and, indirectly, to assess the capacity of this drug to enhance the proportion of liver recipients undergoing successful immunosuppression weaning.

Read the detailed description

Objective:To test in liver transplant recipients identified as non-tolerant whether discontinuation of calcineurin inhibitors followed by 6-month treatment with sirolimus modifies the pattern of expression of the set of genes associated with tolerance

Background: Sirolimus is an immunosuppressive drug used to counter autoimmunity and to prevent acute graft rejection in human and has remarkable tolerance-promoting properties in animal transplant models.

Hypothesis/Specific Aims:We hypothesize that sirolimus promotes tolerogenic pathways in human liver transplantation.

To test in liver transplant recipients identified as non-tolerant whether discontinuation of calcineurin inhibitors followed by 6-month treatment with sirolimus modifies the pattern of expression of the set of genes associated with tolerance
To test in liver transplant recipients identified as non-tolerant whether conversion from calcineurin inhibitors to sirolimus modifies memory type immune responses.
To test in liver transplant recipients identified as non-tolerant whether conversion from calcineurin inhibitor monotherapy to sirolimus affects the frequency, phenotype and function of potentially immunoregulatory peripheral blood lymphocyte subsets
To test in liver transplant recipients identified as non-tolerant whether conversion from calcineurin inhibitors to sirolimus promotes epigenetic changes related to immunoregulation and cancer development/progression

Proposed Methods:Gene expression experiments: we will quantify the expression in peripheral blood of a set of genes previously identified as predictive of successful immunosuppression withdrawal in stable liver transplant recipients. Blood samples will be obtained before and 6 months after conversion to sirolimus treatment. Measurement of gene expression levels will be conducted employing real-time TaqMan PCR. Classification of patients in the tolerant/non-tolerant categories will be conducted utilizing thresholds and predictive algorithms developed in our laboratory.

Immunophenotyping studies: we will quantify in peripheral blood various mononuclear cell subsets implicated in immunoregulatory pathways before and 6 months after conversion to sirolimus treatment. Measurements will be conducted employing flow cytometry.

Functional assays: we will isolate CD4+CD25+ regulatory T cells (Treg) from peripheral blood by Sorter before and 6 months after conversion to sirolimus treatment. Serial dilution experiments will be conduct in an antigen non-specific assay to assess the relative suppressive properties of Tregs. IFNg ELISpot assays will be conducted in parallel employing peripheral blood mononuclear cells as responder cells to measure donor-specific alloimmune responses.

Measurement of DNA-methylation: recipient DNA will be extracted from peripheral blood samples before and after 6-month sirolimus treatment and used to conduct whole-genome methylation studies employing the ILLUMINA array platform.

Expected results: We expect to precisely define the effects of sirolimus on previously identified tolerogenic pathways in humans and, to assess the capacity of this drug to enhance the proportion of liver recipients undergoing successful immunosuppression weaning.

Conditions studied

Liver Transplantation

Keywords

Sirolimus
Liver Transplantation
Tolerance
Immune responses
Allograft tolerance

In context

Lead sponsor

Hospital Clinic of Barcelona is the lead sponsor of 319 studies on the registry; 55 are open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 75 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Age ≥ 18 years and weight ≥ 40 kg
Women of childbearing potential must have a negative serum pregnancy test result before random assignment and must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of randomly assigned treatment. Any woman becoming pregnant during the treatment period must withdraw from the study
Subjects receiving immunosuppressive therapy with a stable regimen of calcineurin inhibitor or a combination of calcineurin inhibitor with corticosteroids and/or antimetabolite therapy for a minimum of 4 weeks prior to randomization
Recipient of a liver transplantation with >3 years follow-up Cockcroft-Gault GFR values ≥ 40 mL/min
Total white blood cell count >3.0 x 109/L (>3,000/mm3), platelet count >75 x109/L (>75,000/mm3), fasting triglycerides \<3.95 mmol/L (\<350 mg/dL), fasting cholesterol \<7.8 mmol/L (\<300 mg/dL). If subjects are currently untreated for elevated cholesterol and/or triglycerides and are excluded from the study based on the above criteria, subjects will be offered antihyperlipidemic therapy.
Stable liver function defined as: a) normal liver function tests (AST, ALT, ALP, GGT) during the previous 6 months; or alternatively b) minor alterations in liver function tests that have not changed over the previous 6 months (AST/ALT \< 2 fold normal levels; ALP \< 1.5 fold normal levels; GGT \< 3 fold normal levels; bilirubin \< 3 mg/dL).
Absence of treatment with interferon for hepatitis C virus infection
Absence of autoimmune diseases requiring immunosuppressive therapy
Absence of autoimmune liver disease as indication for transplantation
Absence of any rejection episodes in the 12 previous months
Peripheral blood gene expression profile characteristic of non-tolerant recipients (likelihood of successful weaning \<5%)
Written, signed, and dated IRB- or IEC-approved informed consent

Exclusion criteria

Exclusion Criteria:

Requirement for treatment with immunosuppressive drugs for any indications other than prevention of rejection
Proteinuria levels > 0.8 g/day
Evidence of systemic infection (e,g., sepsis, bacteremia, pneumonia, etc.) at time of random assignment.
History of documented human immunodeficiency virus infection.
Hypercoagulable states or any history of deep vein thrombosis, HAT, or portal vein thrombosis. (Exception: incidental vascular thrombosis at the time of liver explant, which in the opinion of the investigator, does not place the subject at increased risk of thrombotic events.)
Transplant of other graft in addition to the liver

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 52 participants (estimated)

Study arms

Experimental
Sirolimus
Patients randomized to this arm will discontinue maintenance immunosuppression based on calcineurin inhibitors and start treatment with sirolimus.
Drug: Sirolimus
Active comparator
Calcineurin inhibitor
Patients randomized to this arm will keep the same maintenance immunosuppression based on calcineurin inhibitors.
Drug: Calcineurin inhibitor

Interventions

DrugSirolimus
Switch from calcineurin inhibitor maintenance immunosuppression to sirolimus treatment at the doses needed to reach trough blood levels 8-15 ng/mL.
DrugCalcineurin inhibitor
Patients will maintain the same immunosuppressive regimen based on calcineurin inhibitors. No modifications in the treatment will be conducted.

What researchers measure

Primary outcomes

Effects of conversion from calcineurin inhibitors to sirolimus on tolerance-related biomarkers of tolerance in human liver transplant recipients.
Time frame: 12 months

Study locations

1 of 1 sites recruiting

Hospital Clinic Barcelona, University of Barcelona
Barcelona, 08036, Spain
- Alberto Sanchez-Fueyo, MD · Contact · afueyo@clinic.ub.es · 34-93-2275400
Recruiting

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Dec 17, 2009, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01034345
Lead sponsor: Hospital Clinic of Barcelona
First posted: Dec 17, 2009
Start date: Nov 2009
Primary completion: Nov 2011 (estimated)
Completion: Nov 2011 (estimated)
Last update: Dec 17, 2009

Study contacts

Alberto Sanchez-Fueyo, M.D

Contact

afueyo@clinic.ub.es

34-932275400 ext. 2844

Alberto Sanchez Fueyo, MD

principal investigator · Hospital Clinic Barcelona/IDIBAPS, University of Barcelona

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is status unknown, as verified in Nov 2009. You cannot join it, but the record below documents what was studied.

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