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

NCT01034345 | Unknown Phase 2 DMC

• 1 other identifier: Sirolimus_Liver_Tolerance
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Liver Transplantation

Keywords

Sirolimus; Liver Transplantation; Tolerance; Immune responses; Allograft tolerance

Outcome Measures

Primary Outcomes (1)

• Effects of conversion from calcineurin inhibitors to sirolimus on tolerance-related biomarkers of tolerance in human liver transplant recipients.

  12 months

Study Arms (2)

Sirolimus

EXPERIMENTAL

Patients randomized to this arm will discontinue maintenance immunosuppression based on calcineurin inhibitors and start treatment with sirolimus.

Drug: Sirolimus

Calcineurin inhibitor

ACTIVE COMPARATOR

Patients randomized to this arm will keep the same maintenance immunosuppression based on calcineurin inhibitors.

Drug: Calcineurin inhibitor

Interventions

Sirolimus DRUG

Switch from calcineurin inhibitor maintenance immunosuppression to sirolimus treatment at the doses needed to reach trough blood levels 8-15 ng/mL.

Sirolimus

Calcineurin inhibitor DRUG

Patients will maintain the same immunosuppressive regimen based on calcineurin inhibitors. No modifications in the treatment will be conducted.

Calcineurin inhibitor

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hospital Clinic of Barcelona: lead

Study Sites (1)

Hospital Clinic Barcelona, University of Barcelona

Barcelona, Barcelona, 08036, Spain

RECRUITING

MeSH Terms

Interventions

Sirolimus; Calcineurin Inhibitors

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Alberto Sanchez Fueyo, MD

  Hospital Clinic Barcelona/IDIBAPS, University of Barcelona

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Alberto Sanchez-Fueyo, M.D

CONTACT

34-932275400; afueyo@clinic.ub.es

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: December 16, 2009
• First Posted: December 17, 2009
• Study Start: November 1, 2009
• Primary Completion: November 1, 2011
• Study Completion: November 1, 2011
• Last Updated: December 17, 2009

Record last verified: 2009-11

Locations

ES (1)