EVR and EPO for Liver Transplant Tolerance (EVEREST)

Everolimus and Epoetin for Sustained Liver Transplant Tolerance (EVEREST)(ITN101ST)

This is an open label, single-arm, multicenter phase 1b study of stable adult liver transplant recipients on a tacrolimus (TAC)-based immunosuppression (IS) regimen who will transition from TAC to Everolimus (EVR), receive five doses of EPO and concurrently initiate phased withdrawal from EVR.

The primary objective is to test the safety of administering Everolimus (EVR) and epoetin alfa (EPO) to induce operational tolerance in stable adult liver transplant recipients

Study Overview

• Status: Recruiting
• Conditions: Liver Transplant
• Intervention / Treatment: Drug: Epoetin alfa; Drug: Everolimus

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • University of California San Francisco School of Medicine
      • Contact: Joanne Kwan, BS; Phone Number: 415-476-2574; Email: Joanne.kwan@ucsf.edu
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University Feinberg School of Medicine
      • Contact: Laura Adams, RN; Phone Number: 312-694-0242; Email: Laura.adams@nm.org
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania Medical Center
      • Contact: Mary Kaminski, PA; Phone Number: 215-847-8750; Email: Mary.kaminski@pennmedicine.upenn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subject must be able to understand and provide informed consent
2. 1-10 years post-liver transplant
3. Tacrolimus-containing maintenance immunosuppression (IS) regimen without corticosteroid. Mycophenolate mofetil (MMF) dose must be <=2000 mg daily or mycophenolic acid (MPA) dose<=1440 mg daily (if on MMF or MPA). Tacrolimus level must be <8 ng/ml on the 2 most recent laboratory results within 3 months.
4. Gamma glutamyl transferase (GGT) and alanine transaminase (ALT) <= upper limit of normal (ULN)
5. Estimated glomerular filtration rate (GFR) >=40 mL/min/1.73 m^2 using the CKD-EPI 2021 equation
6. Female subjects of reproductive potential must have a negative pregnancy test upon study entry
7. Female subjects with reproductive potential, must agree to use Food and Drug Administration (FDA)-approved methods of birth control for the duration of the study
8. Subjects must have current vaccinations or documented immunity as per the Division of Allergy, Immunology, and Transplantation (DAIT) vaccine guidance for subjects in transplant trials
9. Negative result of most recent tuberculosis (TB) testing or appropriately completed latent tuberculosis infection (LTBI) therapy. Testing should be conducted using either a purified protein derivative (PPD) or interferon-gamma release assay (i.e., QuantiFERON-TB, T-SPOT.TB). Results from tests performed within 12 months prior to study entry are acceptable in the absence of any intervening exposure to TB. Subjects with a positive test for LTBI must complete appropriate therapy for LTBI. LTBI treatment regimens should be among those endorsed by the Centers for Disease Control and Prevention (CDC)
10. Negative FDA-approved test for human immunodeficiency virus (HIV) diagnosis at screening or as documented in medical record, up to 12 months prior to screening)
11. Negative hepatitis C antibody test at screening or as documented in medical record, up to 12 months prior to screening, in subjects without a history of hepatitis C. If there is a history of treated hepatitis C, then documentation of two consecutive negative hepatitis C virus (HCV) quantitative RNA polymerase chain reaction (PCR) tests separated by at least 3 months is required. Untreated subjects with positive HCV antibody and a single negative quantitative HCV RNA are eligible. Historical negative HCV RNA results are acceptable in the above two cases with positive HCV antibody
12. Negative hepatitis B surface antigen and negative hepatitis B core antibody in subjects without a history of hepatitis B virus (HBV) infection, up to 12 months prior to screening. Those with known hepatitis B infection or positive hepatitis B surface antigen or positive hepatitis B core antibody must be on antiviral therapy and have negative HBV DNA quantitative PCR at screening

Exclusion Criteria:

1. Inability of a subject to comply with study protocol
2. Any medical condition requiring chronic systemic corticosteroid, e.g., severe reactive airways disease. Use of inhaled steroids is not an exclusion
3. Autoimmune cause of liver disease (including autoimmune hepatitis (AIH), primary sclerosing cholangitis, primary biliary cirrhosis)
4. Diagnosis of rejection within 52 weeks prior to screening
5. Donor human leukocyte antigen (HLA) typing unavailable or inadequate for assigning donor-specific antibody (DSA)
6. Need for uninterrupted anticoagulation
7. Known active current or history of invasive fungal infection, or mycobacterial infection within 1 year prior to screening
8. Human immunodeficiency virus (HIV)-positive
9. Serious uncontrolled concomitant major organ disease
10. Recipient of non-liver solid organ or bone marrow transplant
11. Any infection requiring hospitalization and IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks

12. Malignancy within the last 5 years except treated basal and squamous cell cancer of the skin or treated in situ cervical cancer. History of hepatocellular carcinoma in the explanted liver is acceptable provided that

    1. the last alpha fetoprotein obtained within 3 months prior to liver transplantation was < 400 microg/L, and
    2. the recipients' explanted liver did not have evidence of increased risk of recurrent cancer, i.e., explant was within the Milan criteria, with no vascular invasion, and with no cholangiocarcinoma morphology
13. Neutropenia (absolute neutrophil count or ANC <1000 microliter) within 4 weeks prior to study enrollment
14. History of hypersensitivity to Epoetin (EPO) or mammalian Target of Rapamycin inhibitor (mTOR-I)
15. History of angioedema
16. History of hereditary disorders of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. History of lactose intolerance is not an exclusion
17. History of genetic disorders predisposing to thrombosis including but not limited to Factor V Leiden mutation, prothrombin 20210, protein C deficiency, protein S deficiency, antithrombin III deficiency
18. History of venous or arterial thrombosis or thromboembolism, acute MI, or thrombotic stroke except for a history of isolated portal vein thrombosis in the setting of hepatic cirrhosis
19. History of Budd Chiari syndrome
20. Hemoglobin > 13.5 g/dl
21. Plasma fibrinogen or D-dimer level > ULN
22. Planned major surgery within the next 12 months
23. Uncontrolled severe hypertension
24. Uncontrolled clinically significant cardiac arrhythmia
25. Proteinuria with urine protein/creatinine >0.5 g/g
26. Severe hyperlipidemia with total cholesterol >350 mg/dl or triglycerides >1000 mg/dl
27. Current alcohol, drug, or chemical dependency
28. Currently pregnant or nursing
29. Current treatment with an estrogen-containing oral contraceptive, or systemic estrogen replacement therapy
30. Treatment with an immunomodulatory biological drug within 12 weeks of study entry
31. Immunization with live vaccine within 2 weeks of study baseline visit
32. Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational drug, whichever is longer) of screening
33. 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 subject's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm1; Adult liver transplant recipients on a TAC-based IS regimen will transition from Tacrolimus (TAC) to Everolimus (EVR), receive five doses of epoetin alfa (EPO) and concurrently initiate phased withdrawal from EVR. Target accrual for the study is 20 subjects who receive any dose of EPO, and up to 20 donors.

Drug: Epoetin alfa; The dose used in this study is 10,000 units SC every 8 weeks (at study weeks 16, 24, 32, 40 and 48) for five doses; Other Names: EPO; Procrit; Erythropoietin; Drug: Everolimus; The starting dose of EVR will be based on the maintenance TAC dose of the subject at study entry: EVR 1 mg PO BID if TAC dose is <=2 mg BID; EVR 2 mg PO BID if TAC dose is 2.5-7 mg BID; EVR 3 mg PO BID if TAC dose is >7 mg BID The dosage will be adjusted as needed to achieve and maintain EVR trough concentration of 5-8 ng/mL.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of subjects free of opportunistic infection attributed to the investigational study regimen	The primary analysis will be performed using the Intention-to-Treat (ITT) and Per-Protocol (PP) analysis populations, and the proportion will be summarized with a point estimate and a two-sided, 95% confidence interval (CI) calculated using the Clopper-Pearson (exact) method	At 52 weeks post-immunosuppression withdrawal (ISW)
The proportion of subjects free of malignancy attributed to the investigational study regimen	The primary analysis will be performed using the Intention-to-Treat (ITT) and Per-Protocol (PP) analysis populations, and the proportion will be summarized with a point estimate and a two-sided, 95% confidence interval (CI) calculated using the Clopper-Pearson (exact) method	At 52 weeks post-immunosuppression withdrawal (ISW)
The proportion of subjects free of serious adverse events (SAEs) attributed to the investigational study regimen	The primary analysis will be performed using the Intention-to-Treat (ITT) and Per-Protocol (PP) analysis populations, and the proportion will be summarized with a point estimate and a two-sided, 95% confidence interval (CI) calculated using the Clopper-Pearson (exact) method	At 52 weeks post-immunosuppression withdrawal (ISW)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with operational tolerance as defined by no rejection	(clinical or biopsy-proven) since enrollment in the study and a liver biopsy demonstrating histologic stability and absence of rejection per the criteria delineated by the Banff Working Group on Liver Allograft Pathology [1], as assessed by the central pathology laboratory.	At 52 weeks after completion of immunosuppression withdrawal (ISW)
Proportion of subjects with operational tolerance		At 156 weeks after completion of immunosuppression withdrawal (ISW)
Proportion of subjects who are clinically stable off immunosuppression (IS)		At 52 weeks after completion of immunosuppression withdrawal (ISW)
Proportion of subjects who are clinically stable off immunosuppression (IS)		At 156 weeks after completion of immunosuppression withdrawal (ISW)
Incidence of acute rejection	All secondary endpoints (except for the change in eGFR) consider incidences or proportions, and therefore will follow the same analysis approach as the primary safety endpoint. Analysis will be performed using the Intention-to-Treat (ITT) and Per-Protocol (PP) analysis populations The proportion will be summarized with a point estimate and a two-sided, 95% confidence interval (CI) calculated using the Clopper-Pearson (exact) method.	From baseline to 156 weeks post-ISW completion
Severity of acute rejection		From baseline to 156 weeks post-ISW completion
Timing of acute rejection		From baseline to 156 weeks post-ISW completion
Incidence of chronic rejection		From baseline to 156 weeks post-ISW completion
Severity of chronic rejection		From baseline to 156 weeks post-ISW completion
Timing of chronic rejection		From baseline to 156 weeks post-ISW completion
Incidence of de novo class II donor specific antibody (DSA)		From baseline to 156 weeks post-ISW completion
Incidence of graft loss		From baseline to 156 weeks post-ISW completion
Incidence of all-cause mortality		From baseline to 156 weeks post-ISW completion
Incidence of study-related Serious Adverse Event (SAE)s		From baseline to 156 weeks post-ISW completion
Incidence of opportunistic infections		From baseline to 156 weeks post-ISW completion
Incidence of malignancy		From baseline to 156 weeks post-ISW completion
Incidence of Everolimus (EVR) discontinuation due to Adverse Events (AEs)		From baseline to 156 weeks post-ISW completion
Incidence of polycythemia in the study		From baseline to 156 weeks post-ISW completion
Incidence of thromboembolism in the study		From baseline to 156 weeks post-ISW completion
Change in estimated glomerular filtration rate (eGFR)	Change in eGFR will be summarized using descriptive statistics (i.e., number of participants (n), mean, standard deviation (SD), median, first quartile (Q1), third quartile(Q3), minimum and maximum) at baseline, follow-up and for the change score. Follow-up scores will not be imputed. The ITT and PP analysis populations will be used.	From baseline to 156 weeks after completion or failure of ISW

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Sandy Feng, MD, PhD, University of California, San Francisco; Study Chair: Paolo Cravedi, M.D., Ph.D., Icahn School of Medicine at Mount Sinai: Transplantation

Publications and helpful links

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Immune Tolerance Network (ITN)

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: February 12, 2025
• First Submitted That Met QC Criteria: February 12, 2025
• First Posted (Actual): February 18, 2025

Study Record Updates

• Last Update Posted (Actual): April 6, 2026
• Last Update Submitted That Met QC Criteria: April 3, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Everolimus; Tacrolimus; Epoetin alfa; Liver Transplant
• Additional Relevant MeSH Terms: Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Biological Factors; Carbohydrates; Macrolides; Lactones; Intercellular Signaling Peptides and Proteins; Glycoproteins; Glycoconjugates; Sirolimus; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Epoetin Alfa; Everolimus; Erythropoietin
• Other Study ID Numbers: DAIT ITN101ST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: On average, within 24 months after database lock for the trial.
• IPD Sharing Access Criteria: Open access.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No