Liver TransplantationPhase 2NCT00647283
Assessment Of the Safety and Benefit of Prospective Immunosuppressive Drug Withdrawal in Liver Transplantation and Prediction of Operational Tolerance
A Phase 2 study testing Gradual immunosuppression drug withdrawal in people with Liver Transplantation, run by Hospital Clinic of Barcelona at 1 site in Spain.
Trial summary
In liver transplantation up to 20% of recipients can completely discontinue immunosuppressive therapy maintaining normal graft function, and are conventionally considered as operationally tolerant. 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?
- Gradual immunosuppression drug withdrawal
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 1 siteSpain
- Study dates
- Nov 2005to Dec 2012
- 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
- Liver transplantation performed for non-autoimmune liver disease performed at least 3 years before IS weaning.
- Absence of acute and/or chronic rejection episodes during the 12 months before weaning.
- Basal liver biopsy without signs of acute and/or chronic rejection.
- No evidences of autoimmune liver disease.
- Absence of acute and/or chronic rejection episodes during the 12 months before weaning.
- Basal liver biopsy without signs of acute and/or chronic rejection.
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- Low dose immunosuppression (monotherapy with calcineurin inhibitors, mTOR inhibitors or mycophenolate mofetil, or combined therapy with 2 drugs at very low doses).
- Absence of medical or psychological disturbances that preclude the safe performance of the trial.
- Stability of liver graft function, defined as: normal liver function tests (AST, ALT, ALP, GGT) during at least 6 months, or, alternatively, 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 < 2 fold normal levels; bilirubin < 2 mg/dL).
- Patients exhibiting at least one of the following characteristics: a) severe side effects of immunosuppressive drugs (diabetes, renal failure, hyperlipidemia, hypertension); b) risk of neoplasm development defined by history of previous non-hepatocarcinoma neoplasms or history of any of the following risk factors: tobacco or alcohol consumption, age greater than 60 years; c) chronic liver disease due to hepatitis C virus infection in patients not receiving anti-viral treatment.
- Signature of informed consent.
Who cannot join
None listed.
Trial locations and contacts
1 site in 1 country.
Spain1 site
Hospital Clinic Barcelona, University of Barcelona
Barcelona, Barcelona, 08036
About this study
Official title: ASSESSMENT OF THE SAFETY AND BENEFIT OF PROSPECTIVE IMMUNOSUPPRESSIVE DRUG WITHDRAWAL IN LIVER TRANSPLANTATION AND PREDICTION OF OPERATIONAL TOLERANCE
In liver transplantation up to 20% of recipients can completely discontinue immunosuppressive therapy maintaining normal graft function, and are conventionally considered as operationally tolerant. Discontinuation of immunosuppressive drugs in operationally tolerant recipients could lessen the side effects of chronic immunosuppressive therapy. However, this strategy results in the development of rejection in a high proportion of recipients who require lifelong immunosuppression. Thus, there is a need to identify predictive factors of successful drug withdrawal and to define the clinical and histological outcomes of operationally tolerant liver recipients.
The main objective of this study is to establish the safety of attempting immunosuppressive (IS) drug withdrawal in stable liver transplant recipients, using standard clinical, biological and histopathological methods, to screen and follow-up patients, and to confirm the benefit of maintaining immunosuppressive drug interruption in patients who are tolerant to their liver transplant. The secondary objective of this study is to identify predictive factors of operational tolerance and to attempt to develop a multi-parameter "decision rule" to predict patient tolerance or non-tolerance in order to improve patient screening and follow-up. In a diagnostic observational sub-study, peripheral blood and liver tissue samples collected before immunosuppressive drug withdrawal will be employed to validate the diagnostic accuracy of a previously identified set of tolerance biomarkers and to identify potential new biomarkers capable of predicting the outcome of the immunosuppressive withdrawal protocol.
Read the detailed description
- This is a prospective study in which liver transplant recipients on maintenance immunosuppression (IS) will undergo carefully supervised IS weaning over a period of approximately 6-9 months. Patients will be gathered from a consortium of European liver transplant units including: Hospital Clínic Barcelona (Dr A. Sánchez-Fueyo), University Tor Vergata Rome (Dr G.Tisone), University Hospitals Leuven (Dr J.Pirenne). Patients will be followed-up for a total of 48 months after inclusion.
- Patients will be visited every 2-3 weeks, and immunosuppressive drugs will be gradually discontinued with the aim of achieving 50% decrease in drug dosages by month 3, and complete withdrawal by month 6 after initiation of the study. Following drug discontinuation, patients will continue to be followed every 2-3 weeks for 3 months, and monthly thereafter until month 12 after initiation of the study. Liver function tests will be obtained at every clinical follow-up visit. Patients will be considered operationally tolerant if no rejection takes place during the weaning procedure and the 12-month period after complete drug discontinuation. All patients who fail to completely discontinue IS, or in whom drugs have to be reintroduced after a period of complete withdrawal, are considered as IS-dependent or non-tolerant. All biopsies will be blindly reviewed at the end of the study by a single pathologist to ensure diagnostic consistency between the two institutions.
- Management of liver function test alterations:
- Increases in liver function tests below 2-fold normal levels for AST/ALT/GGT, 1.5-fold normal levels for ALP, or 2 mgIdL for bilirubin will result in no further decreases in drug dosages, and performance of new liver function tests in 14 days. Worsening or persistence of liver function test alterations will constitute indication for liver biopsy.
- Increases in liver function tests beyond 2-fold normal levels for AST/ALT/GGT, 1.5-fold normal levels for ALP, or 2 mg/dL for bilirubin will result in liver biopsy.
- Diagnosis of liver graft rejection: will be based on the finding of 2 out of 3 of the following histological criteria: portal inflammation, injury to bile duct epithelium, and endothelitis. The finding of a mixed portal/lobular lymphocytic infiltrate not attributable to any other cause and responding to an increase in immunosuppressive drug doses will also be considered as a rejection.
- Management of rejection episodes: Specific therapy will be decided by the corresponding clinician/institution. Patients undergoing graft rejection will finalize their participation in the study. Worsening of HCV hepatitis or appearance of portal/lobular inflammation not attributable to rejection or viral etiology may also justify withdrawal from the study according to each institution's experience.
- Peripheral blood samples will be collected before weaning starts and every time routine liver function tests are measured. These samples will be employed to conduct microarray gene expression experiments. A portion of all liver biopsies collected will also be cryopreserved to conduct gene expression analyses. This experiments will constitute the basis of an observational sub-study (described in a different protocol) entitled: "Search for the immunological signature of operational tolerance in liver transplantation".
- Sample size has been estimated in order to be able to replicate the microarray gene expression results obtained by our group when comparing tolerant and non-tolerant recipients. In the current project we have followed a novel method recently proposed by Tibshirani et al. and have performed a permutation-based analysis of our pilot microarray data obtained from tolerant and non-tolerant samples. According to this analysis, at least 45 samples (20% tolerant, 80% non-tolerant) are required in order to be able to discriminate between tolerant and non-tolerant HCV-positive samples with a false discovery rate <0.05. Based on this analysis, we expect to enrol a total of 80 patients in order to have at least 60 patients evaluable, who will be randomly allocated into training (45 patients) and testing (15 patients) sets for data analysis purposes.
- Conditions
- Liver Transplantation
- Being tested
- Gradual immunosuppression drug withdrawal
- Keywords
- Liver Transplantation, Tolerance, Allograft tolerance, Immunosuppression minimization, Immunosuppression weaning, Immunological tolerance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gradual immunosuppression drug withdrawalProcedure or surgery
After the obtention of biological samples (peripheral blood, liver tissue), enrolled patients undergo gradual weaning of all immunosuppressive therapy over a 6-9 month period under close medical supervision.
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Stable liver transplant recipients fulfilling inclusion criteria. Receives: Procedure: Gradual immunosuppression drug withdrawal |
What is being measured
The primary outcome is the main question the study is designed to answer.
Operational tolerance defined as liver transplant survival with immunosuppressive drug interruption and without liver transplant rejection after starting drug dose reduction and following 12 months of complete drug discontinuation.
Measured: 18 months
Secondary outcomes (2)
Prevalence of patients developing permanent graft dysfunction as a consequence of immunosuppressive drug withdrawal.
Measured: 48 months
Effects of the immunosuppression weaning procedure on immunosuppression-related side effects (hypertension, diabetes, nephrotoxicity, hyperlipidemia)
Measured: 48 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Mar 2008 (estimated)
- Study startNov 2005
- Primary completionSep 2010
- Study completionDec 2012 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- 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
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital Clinic of Barcelona
- Sponsor type
- University, hospital or other
- Collaborators
- Fondo de Investigacion Sanitaria, European Commission, TcLand Expression S.A.
- Investigators
- Alberto Sanchez-Fueyo, MD, Principal investigator, Hospital Clinic Barcelona / IDIBAPS, Barcelona, SpainGiuseppe Tisone, MD, Study chair, University Tor Vergata, Rome, ItalyJacques Pirenne, MD, Study chair, Abdominal Transplant Surgery Department, University Hospitals Leuven, Belgium
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00647283
- Sponsor's protocol ID
- V-2005-CE512090-O
- Other IDs
- RISET
- Status last verified
- Apr 2011
- First submitted
- 26 Mar 2008
- Last updated
- 20 Apr 2011
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A, Lerut J, Latinne D, Margarit C, Bilbao I, Brouard S, Hernandez-Fuentes M, Soulillou JP, Sanchez-Fueyo A. Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant. 2007 Feb;7(2):309-19. doi: 10.1111/j.1600-6143.2006.01621.x.
PubMed 17241111
Study at a glance
From the registry record, last updated by the sponsor on 20 Apr 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ASSESSMENT OF THE SAFETY AND BENEFIT OF PROSPECTIVE IMMUNOSUPPRESSIVE DRUG WITHDRAWAL IN LIVER TRANSPLANTATION AND PREDICTION OF OPERATIONAL TOLERANCE
- ClinicalTrials.gov ID
- NCT00647283
- Acronym / sponsor ID
- V-2005-CE512090-O
- Conditions
- Liver Transplantation
- Keywords
- Liver Transplantation, Tolerance, Allograft tolerance, Immunosuppression minimization, Immunosuppression weaning, Immunological tolerance
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Hospital Clinic of BarcelonaUniversity, hospital or other
- Collaborators
- Fondo de Investigacion Sanitaria, European Commission, TcLand Expression S.A.
- Study start
- Nov 2005
- Primary completion
- Sep 2010 (actual)
- Study completion
- Dec 2012 (estimated)
- First posted
- 31 Mar 2008 (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 liver transplantation up to 20% of recipients can completely discontinue immunosuppressive therapy maintaining normal graft function, and are conventionally considered as operationally tolerant. Discontinuation of immunosuppressive drugs in operationally tolerant recipients could lessen the side effects of chronic immunosuppressive therapy. However, this strategy results in the development of rejection in a high proportion of recipients who require lifelong immunosuppression. Thus, there is a need to identify predictive factors of successful drug withdrawal and to define the clinical and histological outcomes of operationally tolerant liver recipients.
The main objective of this study is to establish the safety of attempting immunosuppressive (IS) drug withdrawal in stable liver transplant recipients, using standard clinical, biological and histopathological methods, to screen and follow-up patients, and to confirm the benefit of maintaining immunosuppressive drug interruption in patients who are tolerant to their liver transplant. The secondary objective of this study is to identify predictive factors of operational tolerance and to attempt to develop a multi-parameter "decision rule" to predict patient tolerance or non-tolerance in order to improve patient screening and follow-up. In a diagnostic observational sub-study, peripheral blood and liver tissue samples collected before immunosuppressive drug withdrawal will be employed to validate the diagnostic accuracy of a previously identified set of tolerance biomarkers and to identify potential new biomarkers capable of predicting the outcome of the immunosuppressive withdrawal protocol.
Detailed description
- This is a prospective study in which liver transplant recipients on maintenance immunosuppression (IS) will undergo carefully supervised IS weaning over a period of approximately 6-9 months. Patients will be gathered from a consortium of European liver transplant units including: Hospital Clínic Barcelona (Dr A. Sánchez-Fueyo), University Tor Vergata Rome (Dr G.Tisone), University Hospitals Leuven (Dr J.Pirenne). Patients will be followed-up for a total of 48 months after inclusion.
- Patients will be visited every 2-3 weeks, and immunosuppressive drugs will be gradually discontinued with the aim of achieving 50% decrease in drug dosages by month 3, and complete withdrawal by month 6 after initiation of the study. Following drug discontinuation, patients will continue to be followed every 2-3 weeks for 3 months, and monthly thereafter until month 12 after initiation of the study. Liver function tests will be obtained at every clinical follow-up visit. Patients will be considered operationally tolerant if no rejection takes place during the weaning procedure and the 12-month period after complete drug discontinuation. All patients who fail to completely discontinue IS, or in whom drugs have to be reintroduced after a period of complete withdrawal, are considered as IS-dependent or non-tolerant. All biopsies will be blindly reviewed at the end of the study by a single pathologist to ensure diagnostic consistency between the two institutions.
- Management of liver function test alterations:
- Increases in liver function tests below 2-fold normal levels for AST/ALT/GGT, 1.5-fold normal levels for ALP, or 2 mgIdL for bilirubin will result in no further decreases in drug dosages, and performance of new liver function tests in 14 days. Worsening or persistence of liver function test alterations will constitute indication for liver biopsy.
- Increases in liver function tests beyond 2-fold normal levels for AST/ALT/GGT, 1.5-fold normal levels for ALP, or 2 mg/dL for bilirubin will result in liver biopsy.
- Diagnosis of liver graft rejection: will be based on the finding of 2 out of 3 of the following histological criteria: portal inflammation, injury to bile duct epithelium, and endothelitis. The finding of a mixed portal/lobular lymphocytic infiltrate not attributable to any other cause and responding to an increase in immunosuppressive drug doses will also be considered as a rejection.
- Management of rejection episodes: Specific therapy will be decided by the corresponding clinician/institution. Patients undergoing graft rejection will finalize their participation in the study. Worsening of HCV hepatitis or appearance of portal/lobular inflammation not attributable to rejection or viral etiology may also justify withdrawal from the study according to each institution's experience.
- Peripheral blood samples will be collected before weaning starts and every time routine liver function tests are measured. These samples will be employed to conduct microarray gene expression experiments. A portion of all liver biopsies collected will also be cryopreserved to conduct gene expression analyses. This experiments will constitute the basis of an observational sub-study (described in a different protocol) entitled: "Search for the immunological signature of operational tolerance in liver transplantation".
- Sample size has been estimated in order to be able to replicate the microarray gene expression results obtained by our group when comparing tolerant and non-tolerant recipients. In the current project we have followed a novel method recently proposed by Tibshirani et al. and have performed a permutation-based analysis of our pilot microarray data obtained from tolerant and non-tolerant samples. According to this analysis, at least 45 samples (20% tolerant, 80% non-tolerant) are required in order to be able to discriminate between tolerant and non-tolerant HCV-positive samples with a false discovery rate <0.05. Based on this analysis, we expect to enrol a total of 80 patients in order to have at least 60 patients evaluable, who will be randomly allocated into training (45 patients) and testing (15 patients) sets for data analysis purposes.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Procedure: Gradual immunosuppression drug withdrawalStable liver transplant recipients fulfilling inclusion criteria. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Liver transplantation performed for non-autoimmune liver disease performed at least 3 years before IS weaning.
- Absence of acute and/or chronic rejection episodes during the 12 months before weaning.
- Basal liver biopsy without signs of acute and/or chronic rejection.
- No evidences of autoimmune liver disease.
- Absence of acute and/or chronic rejection episodes during the 12 months before weaning.
Key exclusion criteria (0 listed)
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 |
|---|---|---|
| Gradual immunosuppression drug withdrawalAfter the obtention of biological samples (peripheral blood, liver tissue), enrolled patients undergo gradual weaning of all immunosuppressive therapy over a 6-9 month period under close medical supervision. | Procedure or surgery | 1 |
Primary outcome
Operational tolerance defined as liver transplant survival with immunosuppressive drug interruption and without liver transplant rejection after starting drug dose reduction and following 12 months of complete drug discontinuation.
Time frame: 18 months
2 secondary outcomes
Prevalence of patients developing permanent graft dysfunction as a consequence of immunosuppressive drug withdrawal.
Time frame: 48 months
Effects of the immunosuppression weaning procedure on immunosuppression-related side effects (hypertension, diabetes, nephrotoxicity, hyperlipidemia)
Time frame: 48 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Apr 2011.
- Background: PubMed 17241111Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A, Lerut J, Latinne D, Margarit C, Bilbao I, Brouard S, Hernandez-Fuentes M, Soulillou JP, Sanchez-Fueyo A. Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant. 2007 Feb;7(2):309-19. doi: 10.1111/j.1600-6143.2006.01621.x.
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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, Barcelona, Spain
Giuseppe Tisone, MD study chair
University Tor Vergata, Rome, Italy
Jacques Pirenne, MD study chair
Abdominal Transplant Surgery Department, University Hospitals Leuven, Belgium
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 Gradual immunosuppression drug withdrawal 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 11 inclusion and 0 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 20 Apr 2011. 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?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Operational tolerance defined as liver transplant survival with immunosuppressive drug interruption and without liver transplant rejection after starting drug dose reduction and following 12 months of complete drug discontinuation. (time frame: 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00647283, which also lists 1 linked publication.
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 20 Apr 2011.