Everolimus + Epoetin Alfa for Liver Transplant

(EVEREST Trial)

Not yet recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Tacrolimus

Must not be taking: Corticosteroids, Estrogens

Disqualifiers: Autoimmune liver disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of using two drugs, Everolimus and epoetin alfa, in individuals who have undergone a liver transplant. Researchers aim to determine if these drugs can help the immune system better tolerate the new liver. Participants should be stable liver transplant recipients who have used Tacrolimus without steroids for at least a year. The goal is to assess whether this drug combination is safe and effective in aiding the body's acceptance of a transplanted liver. As a Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this new drug combination.

Will I have to stop taking my current medications?

The trial requires participants to transition from their current tacrolimus-based immunosuppression regimen to Everolimus. If you are on tacrolimus, you will need to switch to Everolimus as part of the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both Everolimus and epoetin alfa are generally safe for liver transplant patients. One study found that Everolimus improved kidney function in liver transplant patients with only a few serious side effects. Another study found that treatments based on Everolimus and those based on tacrolimus (TAC) have similar safety levels up to five years post-transplant. While these results are encouraging, it is important to note that this study remains in an early phase, so researchers continue to closely monitor the safety of these treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Everolimus and Epoetin Alfa for liver transplant patients because it offers a unique approach to managing immunosuppression and anemia post-transplant. Unlike standard treatments, which typically rely heavily on Tacrolimus-based regimens, this approach transitions patients to Everolimus, which may reduce some long-term side effects associated with Tacrolimus. Additionally, the inclusion of Epoetin Alfa aims to address anemia, a common issue after transplants, more effectively by stimulating red blood cell production. This dual strategy not only targets the immune response but also directly addresses anemia, potentially improving overall patient outcomes.

What evidence suggests that Everolimus and epoetin alfa could be effective for liver transplant recipients?

In this trial, adult liver transplant recipients will transition from Tacrolimus (TAC) to Everolimus (EVR) and receive epoetin alfa (EPO). Studies have shown that everolimus helps liver transplant patients maintain kidney function without compromising transplant success. It is often combined with lower doses of tacrolimus to enhance outcomes. Research indicates that epoetin alfa effectively increases red blood cell levels, benefiting those with anemia. Evidence also suggests that epoetin alfa may improve transplant acceptance by influencing immune cells. Both treatments have been studied for their potential benefits and safety in liver transplant patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Sandy Feng, MD, PhD

Principal Investigator

University of California, San Francisco

Paolo Cravedi, M.D., Ph.D.

Principal Investigator

Icahn School of Medicine at Mount Sinai: Transplantation

Are You a Good Fit for This Trial?

This trial is for stable adult liver transplant recipients currently on a tacrolimus-based immunosuppression regimen. Specific eligibility details are not provided, but typically participants would need to meet certain health standards and not have conditions that could interfere with the study.

Inclusion Criteria

I am of childbearing age and have a negative pregnancy test.

I understand the study and can give my consent.

I had a liver transplant between 1 and 10 years ago.

Exclusion Criteria

Treatment with any investigational agent within 4 weeks of screening

I was diagnosed with organ rejection less than a year ago.

Inability of a subject to comply with study protocol

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Transition from Tacrolimus (TAC) to Everolimus (EVR), receive five doses of epoetin alfa (EPO), and initiate phased withdrawal from EVR

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of operational tolerance and adverse events

52 weeks

Long-term follow-up

Continued monitoring for incidence of acute rejection and changes in eGFR

104 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Epoetin alfa
• Everolimus

Trial Overview The study involves transitioning patients from tacrolimus to Everolimus (EVR), administering five doses of Epoetin alfa (EPO), and attempting phased withdrawal from EVR to induce operational tolerance in liver transplant recipients.

How Is the Trial Designed?

Group I: Arm1 Experimental Treatment 2 Interventions

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.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

In a randomized trial, the combination of everolimus and reduced-dose tacrolimus (EVR + rTAC) showed equivalent efficacy to standard-dose tacrolimus while providing better renal function in liver transplant recipients.

The cost-effectiveness analysis indicated that EVR + rTAC not only improves survival by an average of 1.92 years and quality-adjusted life years (QALYs) by 1.62 but also presents a favorable cost-effectiveness ratio compared to traditional calcineurin inhibitor therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of everolimus plus reduced tacrolimus in de novo liver-recipients in the Italian setting. Bianic, F., Campbell, R., Damera, V., et al.[2018]

In a systematic review of 8 trials with 1570 liver transplant recipients, everolimus combined with reduced calcineurin inhibitors (CNIs) significantly improved renal function, increasing the glomerular filtration rate (GFR) by 5.59, without increasing the rates of biopsy-proven acute rejection (BPAR), graft loss, or death.

However, this combination therapy was associated with a higher risk of adverse events, indicating that while it benefits kidney function, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of everolimus treatment on liver transplant recipients: A meta-analysis. Guan, TW., Lin, YJ., Ou, MY., et al.[2020]

Everolimus, when used in combination with reduced-dose tacrolimus, has been shown to maintain comparable efficacy in preventing rejection and improving renal function in liver transplant recipients, as demonstrated in a pivotal study of 719 patients.

The introduction of everolimus at 30 days post-transplantation resulted in superior renal function compared to standard tacrolimus exposure, highlighting its potential as a safer alternative in immunosuppressive therapy for liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of everolimus in liver transplantation. Ganschow, R., Pollok, JM., Jankofsky, M., et al.[2021]

In a study of 10 liver transplant recipients with cancer, everolimus treatment resulted in a significantly higher survival rate compared to a historical cohort not receiving the drug, with survival probabilities of 100%, 90%, and 72% at 6, 12, and 24 months, respectively.

Everolimus was found to be safe, with no cases of organ rejection and infrequent severe side effects or infections, suggesting it may be a beneficial option for managing post-transplant neoplasms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of everolimus as a rescue immunosuppressive therapy in liver transplant patients with neoplasms. Gomez-Camarero, J., Salcedo, M., Rincon, D., et al.[2021]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK548904/

Erythropoiesis Stimulating Agents - LiverTox - NCBI Bookshelf (Combined results of 4 controlled trials of epoetin in 297 patients with AIDS found overall increase in hematocrit by 4.6% [vs 0.5% with placebo] ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06832189?cond=Epoetin%20alfa&aggFilters=status:not%20rec%20ava&rank=2

NCT06832189 | EVR and EPO for Liver Transplant Tolerance A type of clinical study in which participants are identified as belonging to study groups and are assessed for biomedical or health outcomes. Participants may ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/10827238/

Erythropoietin response to post-liver transplantation anemia Erythropoietin response appeared appropriate to the degree of anemia in 82% of the liver transplant recipients and blunted in 18%. We conclude that the ability ...

4. insight.jci.org insight.jci.org/articles/view/158856

Linking erythropoietin to Treg-dependent allograft survival ... The data support the conclusion that EPO promotes Treg-dependent murine cardiac allograft survival by crucially altering the phenotype and function of ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2451959622000063

Extended Literature Review of the role of erythropoietin ... A study that included data from a transplant registry showed that high ERI was associated with poor outcomes including death and graft failure [47], [48], [49] ...

6. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT06832189

EVR and EPO for Liver Transplant Tolerance This is an open label, single-arm, multicenter phase 1b study of stable adult liver transplant recipients on a tacrolimus (TAC)-based immunosuppression (IS) ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35962772/

Five-year outcomes in liver transplant patients receiving ... The CERTITUDE study demonstrated that EVR- and TAC-based regimens have comparable efficacy, safety and tolerability up to 5 years post-LTx.

8. withpower.com withpower.com/trial/phase-1-transplantation-liver-5-2025-e51db

Everolimus + Epoetin Alfa for Liver Transplant Everolimus is generally considered safe for liver transplant patients, showing improved kidney function and few severe side effects, though some patients may ...

9. journals.lww.com journals.lww.com/transplantjournal/fulltext/2017/04002/practical_recommendations_for_long_term_management.1.aspx

Practical Recommendations for Long-term Management of. ... Both patient and graft outcomes are continuing to improve, and 1-year patient and graft survival currently exceed 80%. ... However, survival rates gradually ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9826472/

Five‐year outcomes in liver transplant patients receiving ... The study showed that an everolimus‐based regimen was able to preserve renal function up to 5 years post‐liver transplantation without impacting graft survival ...