Expanding Liver Transplant Immunosuppression Minimization Via Everolimus

NCT06280950 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: DAIT CTOT-43
• Study Type: interventional
• Target: 340
• Locations: 1 country
• Sites: 8

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 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.

Conditions

Liver Transplant

Keywords

Liver; Transplant; Everolimus

Outcome Measures

Primary Outcomes (2)

• Percent change in estimated glomerular filtration rate (eGFR) by CKD-EPI 2021 equation. Between Cohorts INT-1 and INT-2

  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

  From Visit 2 to Visit 9 (12 months post-liver transplant)

Secondary Outcomes (22)

• Percent change in estimated Glomerular Filtration Rate (eGFR)

  From Visit 1 to Visit 11 (20 months post-liver transplant)

• Percentage of subjects with treated Biopsy Proven Acute Rejection (tBPAR)

  From Visit 1 to Visit 11 (20 months post-liver transplant)

• Changes in liver graft function: Total bilirubin

  From Visit 1 to Visit 11 (20 months post-liver transplant)

• Changes in liver graft function: Direct bilirubin

  From 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)

Study Arms (3)

Interventional Group 1

EXPERIMENTAL

Participants in this group will slowly reduce their dose of tacrolimus and continue everolimus as their only immunosuppression medication.

Drug: Everolimus; Drug: Tacrolimus (continued reduction)

Interventional Group 2

EXPERIMENTAL

Participants in this group will continue to take reduced Tacrolimus and Everolimus IS regimen.

Drug: Tacrolimus (maintain 50% reduction); Drug: Everolimus

Observational Group

NO INTERVENTION

Participants in this group could not tolerate the addition of everolimus. These participants will not be randomized. * Participants in this group will stop taking everolimus. * Participants in this group will resume taking their tacrolimus +/- mycophenolate compound and prednisone immunosuppression regimen.

Interventions

Tacrolimus (continued reduction) DRUG

* 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

Also known as: FK-506, FR-900506, Prograf, Prograft

Interventional Group 1

Tacrolimus (maintain 50% reduction) DRUG

\- Participants randomized in this cohort maintain initial reduced dose of Tacrolimus and everolimus for study duration.

Also known as: FK-506, FR-900506, Prograf, Prograft

Interventional Group 2

Everolimus DRUG

* 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.

Also known as: Zortress

Interventional Group 1

Eligibility Criteria

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

You may qualify if:

• Subject and/or legal guardian must be able to understand and provide informed consent
• Adult (age greater than or equal to 18 years of age at time of informed consent) recipient of first liver transplant alone (de novo)
• Estimated glomerular filtration rate \>=30 ml/min/1.73m\^2 at enrollment using the CKD-EPI 2021 equation
• Treatment with tacrolimus therapy, with or without mycophenolic acid derivatives and/or corticosteroids
• Female subjects of childbearing potential with negative pregnancy test upon study entry
• All subjects of reproductive potential agreeing to use contraception for the duration of the study
• 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

You may not qualify if:

• Inability or unwillingness of a participant to give written informed consent or comply with study protocol
• Active unresolved systemic viral, bacterial, fungal, or parasitic infection requiring oral or intravenous anti-infective therapy
• History of autoimmune liver disease including autoimmune hepatitis, primary sclerosing cholangitis, and/or primary biliary cirrhosis, or other contraindications to drug withdrawal
• History of non-hepatic autoimmune disease requiring current or future systemic immunosuppressive therapy other than per study protocol
• History post-transplant of Hepatic Artery Thrombosis or Portal Vein Thrombosis.
• History of recurrent cirrhosis after liver transplantation.
• Chronic use of systemic glucocorticoids, biological immunomodulatory therapy, or other immunosuppressive agents other than per study protocol
• History of hepatitis B or C virus infection with detectable viral PCR at enrollment
• History of prior organ transplantation (liver or other type)
• 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
• Active treatment with any mTOR-inhibitor agent (everolimus, sirolimus)
• 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/uL or actively being treated with GCSF; Hb \<8.0; platelet count \<50K); serum triglycerides \> 1000 mg/dL; other per PI)
• 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
• Pregnant on enrollment or plan to become pregnant during the study period
• Participation in another clinical trial that would interfere with this study's procedures and intervention:

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (8)

Mayo Clinic Hospital Arizona (Site #: 71144)

Phoenix, Arizona, 85054, United States

RECRUITING

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

San Francisco, California, 94143, United States

RECRUITING

Northwestern University (Site #: 71110)

Chicago, Illinois, 60611, United States

RECRUITING

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

New York, New York, 10029, United States

RECRUITING

Duke University Medical Center (Site #: 71139)

Durham, North Carolina, 27710, United States

RECRUITING

University of Pennsylvania (Site #: 71111)

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

University of Pittsburgh Medical Center (Site #: 71170)

Pittsburgh, Pennsylvania, 15260, United States

RECRUITING

Baylor Medical Center (Site #: 71153)

Dallas, Texas, 75246, United States

RECRUITING

MeSH Terms

Interventions

Everolimus; Tacrolimus; Benzocaine

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Justin Boike, MD

  Northwestern University Feinberg School of Medicine: Transplantation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tracia Debnam, MS

CONTACT

301-761-7414; Tracia.debnam@nih.gov

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2024
• First Posted: February 28, 2024
• Study Start: September 12, 2024
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2030
• Last Updated: May 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: 24 Months after database lock for the trial
• Access Criteria: Open Access

Locations

US (8)