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 participants will be placed into an observational group and will remain on their current post-transplant medications. The duration of the study from time of enrollment is 18-20 months.
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 reduction of tacrolimus with the addition of everolimus. If everolimus is tolerated, subjects will be randomized 2:1 into one of two interventional arms. The first interventional arm will undergo a stepwise reduction of tacrolimus and be on everolimus monotherapy for the remainder of the study. The second interventional arm will remain on the initial reduced tacrolimus dose and everolimus. If subjects prior to randomization are unable to tolerate everolimus, these subjects will be placed in the observational group. These subjects will stop taking everolimus and resume their immunosuppression therapy prior to study enrollment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
340
* The first step is the addition of everolimus to participants in this group pre-randomization. * Participants on a mycophenolate compound will stop taking it within 7 days of initiating everolimus, either by immediate discontinuation or a 7-day taper. * Participants taking prednisone will taper off prednisone by 6 months post-transplant. * The second step is tacrolimus minimization and withdrawal to everolimus monotherapy in this group after randomization.
* Participants randomized in this cohort will have their tacrolimus dose reduced by 50% following randomization. * They will maintain this daily dose for 4 weeks/1 month (28-30 days). Tacrolimus withdrawal will occur in intervals of 30 days or 4 weeks. * Each subsequent reduction will be based on LFT stability over the prior time interval before the next reduction
\- Participants randomized in this cohort maintain initial reduced dose of Tacrolimus and everolimus for study duration.
* The first step is the addition of everolimus to participants in the interventional group pre-randomization. * Participants on a mycophenolate compound will stop taking it within 7 days of initiating everolimus, either by immediate discontinuation or a 7-day taper. * Participants taking prednisone will taper off prednisone by 6 months post-transplant. * The second step is to continue on the reduced tacrolimus and everolimus regimen.
Mayo Clinic Hospital Arizona (Site #: 71144)
Phoenix, Arizona, United States
RECRUITINGRonald Regan at UCLA Medical Center (Site #: 71123)
Los Angeles, California, United States
NOT_YET_RECRUITINGUniversity of California, San Diego (Site #: 71179)
San Diego, California, United States
NOT_YET_RECRUITINGUniversity of California, San Francisco (Site #: 71108)
San Francisco, California, United States
RECRUITINGNorthwestern University (Site #: 71110)
Chicago, Illinois, United States
RECRUITINGUniversity of Michigan (Site #: 71154)
Ann Arbor, Michigan, United States
RECRUITINGIcahn School of Medicine at Mount Sinai (Site #: 71115)
New York, New York, United States
RECRUITINGDuke University Medical Center (Site #: 71139)
Durham, North Carolina, United States
RECRUITINGUniversity of Pennsylvania (Site #: 71111)
Philadelphia, Pennsylvania, United States
RECRUITINGUniversity of Pittsburgh Medical Center (Site #: 71170)
Pittsburgh, Pennsylvania, United States
RECRUITING...and 2 more locations
Percent change in estimated glomerular filtration rate (eGFR) by CKD-EPI 2021 equation. Between Cohorts INT-1 and INT-2
Time frame: From Visit 2 to Visit 9 (12 months post-liver transplant)
Proportion of subjects with treated Biopsy Proven Acute Rejection (tBPAR) per local pathology. Between cohorts INT-1 and INT-2
Time frame: From Visit 2 to Visit 9 (12 months post-liver transplant)
Percent change in estimated Glomerular Filtration Rate (eGFR)
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Percentage of subjects with treated Biopsy Proven Acute Rejection (tBPAR)
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Total bilirubin
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Direct bilirubin
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Alanine Aminotransaminase (ALT)
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Aspartate Aminotransferase (AST)
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Changes in liver graft function: Alkaline Phosphatase
Time frame: From 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 graft
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Time to all-cause mortality
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects experiencing a Major Adverse Cardiac Event (MACE)
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects experiencing infection requiring hospitalization
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects experiencing any malignancy
Time frame: From 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 equation
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing any major immunosuppressive therapy complications
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset peripheral edema
Time frame: From 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.
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset oral/gastrointestinal ulcerations
Time frame: 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.
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset pneumonitis
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing new onset hepatic artery thrombosis
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing other adverse events deemed
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
Proportion of subjects developing any adverse events related to everolimus therapy
Time frame: From Visit 1 to Visit 11 (20 months post-liver transplant)
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