Everolimus + Epoetin Alfa for Liver Transplant

(EVEREST Trial)

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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

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

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.

What data supports the effectiveness of the drug combination Everolimus and Epoetin Alfa for liver transplant patients?

Research shows that Everolimus, when used with reduced-dose tacrolimus, is effective in liver transplant patients, maintaining good kidney function and preventing organ rejection. Although Epoetin Alfa is not specifically mentioned in these studies, it is commonly used to treat anemia, which can be a concern for transplant patients. ^{1 2 3 4 5}

Is the combination of Everolimus and Epoetin Alfa safe for liver transplant patients?

Everolimus is generally considered safe for liver transplant patients, showing improved kidney function and few severe side effects, though some patients may experience issues like edema (swelling) and dyslipidemia (abnormal cholesterol levels). However, specific safety data for the combination of Everolimus and Epoetin Alfa in liver transplants is not available, so further studies are needed. ^{2 4 5 6 7}

How is the drug combination of Everolimus and Epoetin Alfa unique for liver transplant patients?

The combination of Everolimus and Epoetin Alfa for liver transplant patients is unique because Everolimus, an mTOR inhibitor, helps reduce the need for calcineurin inhibitors, which can cause kidney problems, while Epoetin Alfa is used to manage anemia. This approach aims to improve kidney function and manage anemia, which are common issues in liver transplant patients. ^{2 3 4 7 8}

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

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Arm1 Experimental Treatment 2 Interventions

Adult liver transplant recipients on a TAC-based IS regimen will transition from Tacrolimus (TAC) to Everolimus (EV), receive five doses of epoetin alfa 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+

Findings from Research

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]

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 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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Multiple indications for everolimus after liver transplantation in current clinical practice. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of everolimus plus reduced tacrolimus in de novo liver-recipients in the Italian setting. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Safety, tolerability, and efficacy of everolimus in de novo liver transplant recipients: 12- and 36-month results. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

The role of everolimus in liver transplantation. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of everolimus treatment on liver transplant recipients: A meta-analysis. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Use of everolimus as a rescue immunosuppressive therapy in liver transplant patients with neoplasms. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Early Everolimus When Calcineurin Inhibitors Are Not Recommended in Orthotopic Liver Transplantation. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Impact of Everolimus-based Immunosuppression on Renal Function in Liver Transplant Recipients. [2021]