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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether liver transplant patients can safely switch from the usual anti-rejection drug, tacrolimus, to everolimus (also known as Afinitor, Votubia, or Zortress). The goal is to determine if everolimus better protects kidney function compared to tacrolimus. Participants will be divided into groups; some will reduce tacrolimus while increasing everolimus, while others will continue their current medications. This study suits those who have recently had a liver transplant and are currently taking tacrolimus. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that everolimus is safe for liver transplant patients. One study found that everolimus helped maintain stable kidney function for up to five years without harming the transplanted liver. Another study found that combining everolimus with a lower dose of tacrolimus (a drug that prevents organ rejection) was as safe as using the standard dose of tacrolimus alone, but it improved kidney health.

The FDA has also approved everolimus for use in other types of transplants, indicating that its safety is well-documented. While all medications can have side effects, extensive safety information is available for everolimus in transplant patients. Overall, everolimus appears well-tolerated and helps protect kidney health in liver transplant recipients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Everolimus for liver transplant patients because it offers a novel approach to immunosuppression. Unlike the standard treatment, which typically involves high doses of tacrolimus, Everolimus allows for a reduction in tacrolimus while maintaining immune system control. This can potentially reduce the risk of tacrolimus-related side effects, such as kidney damage. Additionally, Everolimus targets a different pathway in the immune system, providing a unique mechanism of action that could improve outcomes for transplant patients.

What evidence suggests that everolimus could be an effective treatment for liver transplant patients?

Research has shown that everolimus can benefit liver transplant patients, especially when combined with lower doses of tacrolimus. In this trial, participants in Interventional Group 1 will gradually reduce their tacrolimus dose and continue everolimus as their sole immunosuppression medication. Participants in Interventional Group 2 will maintain a reduced tacrolimus and everolimus regimen. One study found that patients taking everolimus with less tacrolimus had better kidney health compared to those taking the usual amount of tacrolimus. Another study found that everolimus is safe and effective for up to two years after a liver transplant. Everolimus can help reduce the risk of kidney problems, which can be a concern with standard anti-rejection medications. Overall, these findings suggest that everolimus could be a good option for preventing organ rejection after a liver transplant. ^{2 6 7 8 9}

Who Is on the Research Team?

Justin Boike, MD

Principal Investigator

Northwestern University Feinberg School of Medicine: Transplantation

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5265697/

Use of Everolimus in Liver Transplantation Three-year outcomes in de novo liver transplant patients receiving everolimus with reduced tacrolimus: follow-up results from a randomized, multicenter study.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01888432

Efficacy and Safety of Everolimus in Liver Transplant ... The purpose of this trial was to demonstrate the efficacy and safety of everolimus in combination with reduced tacrolimus, compared to tacrolimus control, in ...

3. journals.lww.com journals.lww.com/transplantjournal/citation/2008/07271/everolimus_is_effective_and_safe_in_a_six_month,.281.aspx

everolimus is effective and safe in a six-month, randomized Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0955470X21000616

An overview of the efficacy and safety of everolimus in ... In terms of everolimus-facilitated CNI withdrawal in liver transplant recipients, the PROTECT study demonstrated improved renal function with an everolimus- ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1111/ctr.14957

Safety and efficacy of everolimus initiation from the first ... Use of initial/early everolimus seems to be effective with a satisfactory safety profile, making its administration a reasonable therapeutic option in the LT ...

6. 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 ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33741847/

Efficacy and Safety of Everolimus With Reduced ... Conclusions: EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients ...

8. novartis.com novartis.com/us-en/sites/novartis_us/files/zortress.pdf

Zortress® (everolimus) tablets, for oral use The data described below reflect exposure to Zortress starting 30 days after transplantation in an open-label, randomized trial of liver transplant patients.

9. journals.lww.com journals.lww.com/transplantjournal/fulltext/2021/07000/efficacy_and_safety_of_everolimus_with_reduced.23.aspx

Efficacy and Safety of Everolimus With Reduced Tacrolimus... Three-year outcomes in de novo liver transplant patients receiving everolimus with reduced tacrolimus: follow-up results from a randomized, multicenter study.