Everolimus for Liver Transplant

(ELIMINATE Trial)

Recruiting at 8 trial locations

Overseen By Tracia Debnam, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

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

Must be taking: Tacrolimus

Must not be taking: mTOR inhibitors

Disqualifiers: Infections, Autoimmune diseases, Thrombosis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 18-20 months

340 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that some participants will remain on their current post-transplant medications. It's best to discuss your specific situation with the study team.

What data supports the effectiveness of the drug Everolimus for liver transplant patients?

Everolimus, when used with reduced-dose tacrolimus and steroids, has been shown to be effective in preventing organ rejection in liver transplant patients, while also improving kidney function compared to standard tacrolimus treatment. Studies have demonstrated its efficacy in both new and ongoing liver transplant cases, with a significant renal benefit and acceptable safety profile. ^{1 2 3 4 5}

Is everolimus safe for liver transplant patients?

Everolimus is generally considered safe for liver transplant patients, showing an acceptable safety profile and improved kidney function when used with reduced doses of other medications. It has been used successfully in various transplant settings with few severe side effects and infections. ^{1 2 3 6 7}

How is the drug everolimus unique for liver transplant patients?

Everolimus is unique for liver transplant patients because it can be used with a lower dose of tacrolimus, which helps maintain kidney function better than standard tacrolimus doses. This combination provides effective protection against organ rejection while reducing the risk of kidney problems often associated with long-term use of other drugs. ^{1 2 5 8 9}

What is the purpose of this trial?

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.

Research Team

Justin Boike, MD

Principal Investigator

Northwestern University Feinberg School of Medicine: Transplantation

Eligibility Criteria

This trial is for liver transplant recipients looking to minimize anti-rejection medication. Participants should be 2-3 months post-transplant and willing to potentially switch from tacrolimus to everolimus therapy. The study excludes those not stable on current medications or with conditions that may interfere with the trial.

Inclusion Criteria

Subject and/or legal guardian must be able to understand and provide informed consent

I have received my first liver transplant.

I am currently on tacrolimus, possibly with mycophenolic acid or steroids.

Exclusion Criteria

Participation in another clinical trial that would interfere with this study's procedures and intervention:

Any other procedure or intervention, in the investigator's opinion would interfere with this study

I have had an organ transplant in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-3 months

Treatment

Participants undergo tacrolimus reduction with the addition of everolimus. If tolerated, they are randomized into interventional arms for further treatment adjustments.

18-20 months

Follow-up

Participants are monitored for safety, efficacy, and tolerability of the treatment regimen after the main intervention phase.

4-6 months

Treatment Details

Interventions

• Everolimus

Trial Overview The study tests if taking patients off tacrolimus (an anti-rejection drug) and using everolimus instead can better preserve kidney function after a liver transplant. It's a randomized trial where some will reduce their current meds, while others will switch to everolimus.

Participant Groups

Group I: Interventional Group 2 Experimental Treatment 2 Interventions

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

Group II: Interventional Group 1 Experimental Treatment 2 Interventions

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

Group III: Observational Group Active Control 1 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.

Everolimus is already approved in United States, European Union for the following indications:

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

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

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]

Everolimus, when used in combination with a reduced dosage of tacrolimus, is effective for preventing organ rejection in adult liver transplant recipients without compromising efficacy compared to standard tacrolimus exposure.

Patients receiving everolimus plus reduced-exposure tacrolimus showed significantly better renal function starting from 6 weeks after transplantation, and the combination therapy has an acceptable tolerability profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus: a guide to its use in liver transplantation. Keating, GM., Lyseng-Williamson, KA.[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 91 liver transplant patients, early use of everolimus (started within 3-5 days post-transplant) demonstrated a low acute rejection rate of 6.6% and maintained stable renal function over an average follow-up of 4.6 years.

Patient survival rates at one, three, and five years were 80.5%, 74.2%, and 70.5%, respectively, indicating that everolimus combined with low-dose calcineurin inhibitors is a safe and effective immunosuppressive strategy after liver transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Initiation of Everolimus After Liver Transplantation: A Single-Center Experience. Herden, U., Galante, A., Fischer, L., et al.[2019]

Everolimus, an mTOR inhibitor, can be introduced from week 4 after liver transplantation, providing significant renal benefits without compromising immunosuppressive efficacy, making it a valuable option for managing renal dysfunction in transplant patients.

The use of everolimus is associated with a low rate of acute rejection when switching from calcineurin inhibitors, and it may also help prevent recurrence of hepatocellular cancer and other malignancies, although further research is needed to solidify these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of everolimus in liver transplantation: The French experience. Dumortier, J., Dharancy, S., Calmus, Y., et al.[2018]

In a study of 10 lung transplant recipients who were converted to everolimus, the drug was found to be effective and safe over a long-term follow-up period, with stable renal function and no rejection episodes reported.

While there were some adverse events, including infections and two cases of neoplasia, the overall results suggest that everolimus can be a viable option for lung transplant patients when used alongside low doses of calcineurin inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term use of everolimus in lung transplant patients. Parada, MT., Alba, A., Sepúlveda, C., et al.[2015]

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]

In a study of 50 liver transplant patients followed for 12 months, using everolimus without corticosteroids or induction therapy resulted in an 80% survival rate for both patients and grafts, with stable liver function and no cases of rejection or graft loss.

The regimen was well-tolerated, with only 10% of patients developing dyslipidemia, suggesting that this approach may reduce the adverse effects associated with traditional higher-dose immunosuppression therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of mammalian target of rapamycin inhibitors ab initio after liver transplantation without corticosteroids or induction therapy. Manzia, TM., Angelico, R., Toti, L., et al.[2022]

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]

References

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

The role of everolimus in liver transplantation. [2021]

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

Everolimus: a guide to its use in liver transplantation. [2021]

3. England pubmed.ncbi.nlm.nih.gov

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

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

Early Initiation of Everolimus After Liver Transplantation: A Single-Center Experience. [2019]

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

Use of everolimus in liver transplantation: The French experience. [2018]

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

Long-term use of everolimus in lung transplant patients. [2015]

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

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

8. Netherlands pubmed.ncbi.nlm.nih.gov

The efficacy and safety of mammalian target of rapamycin inhibitors ab initio after liver transplantation without corticosteroids or induction therapy. [2022]

9. England pubmed.ncbi.nlm.nih.gov

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