Liver TransplantationPhase 2NCT01034345
Effect of Rapamycin on Tolerance-related Biomarkers on Stable Liver Transplant Recipients
A Phase 2 study testing Sirolimus and Calcineurin inhibitor in people with Liver Transplantation, run by Hospital Clinic of Barcelona at 1 site in Spain.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Liver Transplantation
- What is being tested?
- Sirolimus and Calcineurin inhibitor
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 52 participants
- Where
- 1 siteSpain
- Study dates
- Nov 2009to Nov 2011
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
Spain1 site, 1 recruiting
- Recruiting
Hospital Clinic Barcelona, University of Barcelona
Barcelona, Barcelona, 08036
Alberto Sanchez-Fueyo, MD, 34-93-2275400 ext. 2844, afueyo@clinic.ub.es
About this study
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
- Liver Transplantation
- Being tested
- Sirolimus, Calcineurin inhibitor
- Keywords
- Sirolimus, Liver Transplantation, Tolerance, Immune responses, Allograft tolerance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SirolimusDrug
Switch from calcineurin inhibitor maintenance immunosuppression to sirolimus treatment at the doses needed to reach trough blood levels 8-15 ng/mL.
Calcineurin inhibitorDrug
Patients will maintain the same immunosuppressive regimen based on calcineurin inhibitors. No modifications in the treatment will be conducted.
| Study group | Role | What they receive |
|---|---|---|
| Sirolimus | Experimental | Patients randomized to this arm will discontinue maintenance immunosuppression based on calcineurin inhibitors and start treatment with sirolimus. Receives: Drug: Sirolimus |
| Calcineurin inhibitor | Active comparator | Patients randomized to this arm will keep the same maintenance immunosuppression based on calcineurin inhibitors. Receives: Drug: Calcineurin inhibitor |
What is being measured
The primary outcome is the main question the study is designed to answer.
Effects of conversion from calcineurin inhibitors to sirolimus on tolerance-related biomarkers of tolerance in human liver transplant recipients.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Dec 2009 (estimated)
- Study startNov 2009
- Primary completionNov 2011 (estimated)
- Study completionNov 2011 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Liver TransplantationStudies of the same condition, open and under way.
- More trials run by Hospital Clinic of BarcelonaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 52 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital Clinic of Barcelona
- Sponsor type
- University, hospital or other
- Investigators
- Alberto Sanchez Fueyo, MD, Principal investigator, Hospital Clinic Barcelona/IDIBAPS, University of Barcelona
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01034345
- Sponsor's protocol ID
- Sirolimus_Liver_Tolerance
- Status last verified
- Nov 2009
- First submitted
- 16 Dec 2009
- Last updated
- 17 Dec 2009
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Rapamycin on Tolerance-related Biomarkers on Stable Liver Transplant Recipients
- ClinicalTrials.gov ID
- NCT01034345
- Acronym / sponsor ID
- Sirolimus_Liver_Tolerance
- Conditions
- Liver Transplantation
- Keywords
- Sirolimus, Liver Transplantation, Tolerance, Immune responses, Allograft tolerance
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 52 participants (estimated)
- Lead sponsor
- Hospital Clinic of BarcelonaUniversity, hospital or other
- Study start
- Nov 2009
- Primary completion
- Nov 2011 (estimated)
- Study completion
- Nov 2011 (estimated)
- First posted
- 17 Dec 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sirolimus | Experimental | Drug: SirolimusPatients randomized to this arm will discontinue maintenance immunosuppression based on calcineurin inhibitors and start treatment with sirolimus. |
| Calcineurin inhibitor | Active comparator | Drug: Calcineurin inhibitorPatients randomized to this arm will keep the same maintenance immunosuppression based on calcineurin inhibitors. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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.
Key exclusion criteria (6 listed)
- 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.)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SirolimusSwitch from calcineurin inhibitor maintenance immunosuppression to sirolimus treatment at the doses needed to reach trough blood levels 8-15 ng/mL. | Drug | Sirolimus |
| Calcineurin inhibitorPatients will maintain the same immunosuppressive regimen based on calcineurin inhibitors. No modifications in the treatment will be conducted. | Drug | Calcineurin inhibitor |
Primary outcome
Effects of conversion from calcineurin inhibitors to sirolimus on tolerance-related biomarkers of tolerance in human liver transplant recipients.
Time frame: 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Dec 2009.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alberto Sanchez Fueyo, MD principal investigator
Hospital Clinic Barcelona/IDIBAPS, University of Barcelona
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Sirolimus and Calcineurin inhibitor in people with Liver Transplantation, run by Hospital Clinic of Barcelona at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 17 Dec 2009. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Alberto Sanchez-Fueyo, M.D (34-932275400 ext. 2844, afueyo@clinic.ub.es), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Effects of conversion from calcineurin inhibitors to sirolimus on tolerance-related biomarkers of tolerance in human liver transplant recipients. (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2009; AzTrials last refreshed its copy on 7 Nov 2026.