Expanding Liver Transplant Immunosuppression Minimization Via Everolimus

Registration Number
NCT06280950
Lead Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Brief Summary

This is a study to determine the safety, efficacy, and tolerability of taking away the anti-rejection medicine, tacrolimus, in liver transplant recipients in conjunction with everolimus monotherapy to preserve renal function. Two hundred - seventy (270) subjects will be randomized 2:1 into one of two groups between 2-3 months post-transplant. Seventy partici...

Detailed Description

This study is a multicenter 2:1 randomized nonblinded phase II interventional clinical trial in liver transplant recipients. The primary objective is to determine the safety, efficacy, and tolerability of tacrolimus minimization and eventual withdrawal in conjunction with everolimus monotherapy to preserve renal function. Study subjects will undergo first re...

Recruitment & Eligibility

Status
RECRUITING
Sex
All
Target Recruitment
340
Inclusion Criteria
  1. Subject and/or legal guardian must be able to understand and provide informed consent
  2. Adult recipient of first liver transplant alone (de novo)
  3. Estimated glomerular filtration rate >=30 ml/min/1.73m^2 at enrollment using the CKD-EPI 2021 equation
  4. Treatment with tacrolimus therapy, with or without mycophenolic acid derivatives and/or corticosteroids
  5. Female subjects of childbearing potential with negative pregnancy test upon study entry
  6. All subjects of reproductive potential agreeing to use contraception for the duration of the study
  7. Previous vaccination or documented immunity to varicella, measles, hepatitis B, pneumococcus, influenza, zoster (if >=19 years old), and 2019-nCoV (COVID-19) as outlined in the DAIT Vaccination Guideline
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Exclusion Criteria
  1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol

  2. Active unresolved systemic viral, bacterial, fungal, or parasitic infection requiring oral or intravenous anti-infective therapy

  3. History of autoimmune liver disease including autoimmune hepatitis, primary sclerosing cholangitis, and/or primary biliary cirrhosis, or other contraindications to drug withdrawal

  4. History of non-hepatic autoimmune disease requiring current or future systemic immunosuppressive therapy other than per study protocol

  5. History of Hepatic Artery Thrombosis or Portal Vein Thrombosis.

  6. Chronic use of systemic glucocorticoids, biological immunomodulatory therapy, or other immunosuppressive agents other than per study protocol

  7. History of hepatitis B or C virus infection with detectable viral PCR at enrollment

  8. History of prior organ transplantation (liver or other type)

  9. History of >= 2 biopsy-proven acute cellular rejection episodes of any severity, >=1 moderate to severe rejection episode (histologically defined or requiring lymphodepletion therapy), or >= 1 antibody- mediated rejection episode

  10. Active treatment with any mTOR-inhibitor agent (everolimus, sirolimus)

  11. Contraindication to treatment with everolimus (open wound or wound infection; urine protein: creatinine ratio > 0.5; significant pancytopenia (any of the following: WBC <1.5 K/uL or ANC <1000 cells/microL or actively being treated with GCSF; Hb <8.0; platelet count <50K); serum triglycerides > 1000 mg/dL; other per PI)

  12. Abnormal liver function tests on study entry: Total Bilirubin (TB)>1.5 mg/dL and Direct Bilirubin (DB) >1.0 mg/dL, Alkaline Phosphatase (AP) >200 U/L, and Alanine Aminotransaminase (ALT)>60 U/L

  13. Pregnant on enrollment or plan to become pregnant during the study period

  14. Participation in another clinical trial that would interfere with this study's procedures and intervention:

    1. Use of investigational biologic or drug (within 8 weeks of study enrollment)
    2. Additional blood collection that would exceed research blood draw limits
    3. Any other procedure or intervention, in the investigator's opinion would interfere with this study
  15. Received live attenuated vaccine(s) within 2 months of enrollment

  16. Current, diagnosed, mental illness or current, diagnosed, or self-reported drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study

  17. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Interventional Group 2Tacrolimus (maintain 50% reduction)Participants in this group will continue to take reduced Tacrolimus and Everolimus IS regimen.
Interventional Group 1Tacrolimus (continued reduction)Participants in this group will slowly reduce their dose of tacrolimus and continue everolimus as their only immunosuppression medication.
Interventional Group 1EverolimusParticipants in this group will slowly reduce their dose of tacrolimus and continue everolimus as their only immunosuppression medication.
Interventional Group 2EverolimusParticipants in this group will continue to take reduced Tacrolimus and Everolimus IS regimen.
Primary Outcome Measures
NameTimeMethod
Proportion of subjects with treated Biopsy Proven Acute Rejection (tBPAR) per local pathology. Between cohorts INT-1 and INT-2From Visit 2 to Visit 9 (12 months post-liver transplant)
Percent change in estimated glomerular filtration rate (eGFR) by CKD-EPI 2021 equation. Between Cohorts INT-1 and INT-2From Visit 2 to Visit 9 (12 months post-liver transplant)
Secondary Outcome Measures
NameTimeMethod
Changes in liver graft function: Direct bilirubinFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects experiencing any malignancyFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing any major immunosuppressive therapy complicationsFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset pneumonitisFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing any adverse events related to everolimus therapyFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing severe Estimated Glomerular Filtration Rate (eGFR) deterioration >40 percent from baseline using the CKD-EPI 2021 equationFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Percent change in Estimated Glomerular Filtration Rate (eGFR) in Renal functionFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Percentage of subjects with treated Biopsy Proven Acute Rejection (tBPAR) in Liver FunctionFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Total bilirubinFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Alanine Aminotransaminase (ALT)From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset hepatic artery thrombosisFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing other adverse events deemedFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Aspartate Aminotransferase (AST)From Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Alkaline PhosphataseFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Time to graft failure in liver function defined as relisting for transplantation, re-transplantation itself or death with failed graftFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects experiencing a Major Adverse Cardiac Event (MACE)From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects experiencing infection requiring hospitalizationFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset peripheral edemaFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset oral/gastrointestinal ulcerationsFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Time to all-cause mortalityFrom Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset cytopenia deemed WBC <3.0x10^9 /L, Hb <8.0 g/dL, or platelets <50 x 10^9/L.From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset gastrointestinal symptoms (nausea, vomiting, abdominal pain, or diarrhea) related to everolimus therapy.From Visit 1 to Visit 11 (20 months post-liver transplant)

Trial Locations

Locations (8)

Mayo Clinic Hospital Arizona (Site #: 71144)

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Phoenix, Arizona, United States

University of California, San Francisco (Site #: 71108)

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San Francisco, California, United States

Northwestern University (Site #: 71110)

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Chicago, Illinois, United States

Icahn School of Medicine at Mount Sinai (Site #: 71115)

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New York, New York, United States

Duke University Medical Center (Site #: 71139)

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Durham, North Carolina, United States

University of Pennsylvania (Site #: 71111)

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Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center (Site #: 71170)

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Pittsburgh, Pennsylvania, United States

Baylor Medical Center (Site #: 71153)

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Dallas, Texas, United States

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