Extended-Release Tacrolimus for Liver Transplant Complications

Overseen By Nadia Shular, RN

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Alberta

Must be taking: Calcineurin inhibitors

Disqualifiers: Congenital long QT syndrome, chronic kidney disease, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

94 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new version of a common medication, Envarsus (an extended-release form of tacrolimus), to determine if it causes fewer side effects for liver transplant recipients. The researchers aim to assess whether this new formulation is safer and as effective as the standard medication, Prograf, particularly regarding liver function and reducing hospital visits. Individuals who have had a liver transplant at the University of Alberta and do not have certain health issues, such as severe kidney problems, might be suitable for this study. As a Phase 4 trial, this study involves an FDA-approved treatment and seeks to understand its benefits for more patients, offering a chance to contribute to valuable research.

Do I need to stop my current medications for this trial?

The trial information does not specify if you need to stop your current medications. It's best to discuss this with the trial coordinators or your doctor.

What is the safety track record for these treatments?

Research has shown that Envarsus, a new version of the drug tacrolimus, might cause fewer side effects than the older version, Prograf. Studies have found that people using Envarsus have a lower chance of treatment failure. For example, after one year, the risk of treatment failure is 9% lower compared to those using Prograf. However, Envarsus is not approved by the FDA for liver transplants due to concerns about increased risks for certain groups, such as women.

For other types of transplant patients, the most common side effects of Envarsus include diarrhea, low red blood cell count (anemia), and urinary tract infections. This suggests that while some risks exist, they might be fewer than with the older version. It is always important to consider the benefits and risks and consult a healthcare provider before choosing a treatment. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Envarsus is unique because it offers a convenient, extended-release formulation for managing liver transplant complications. Unlike the standard of care, Prograf, which requires twice-daily dosing, Envarsus is taken just once a day, potentially improving patient adherence. Additionally, the extended-release mechanism of Envarsus ensures a smoother, more consistent delivery of the medication throughout the day, which may lead to better outcomes and reduced side effects. Researchers are excited about these features, as they could make the routine medication regimen easier for liver transplant patients, enhancing their overall quality of life.

What evidence suggests that Envarsus might be an effective treatment for liver transplant complications?

In this trial, participants will receive either Envarsus or Prograf to manage complications after a liver transplant. Research has shown that Envarsus, a long-acting version of tacrolimus, can effectively manage post-transplant issues. One study found that people taking Envarsus had a 9% lower chance of treatment failure after one year compared to those taking Prograf, a more common drug. After two years, this chance of failure decreased by 17%. Envarsus may also cause fewer side effects, which is important for better kidney health and overall patient well-being. Although the FDA has not specifically approved Envarsus for liver transplants, these findings suggest it could be a promising option. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

This trial is for adults who had a liver transplant at the University of Alberta. It's not for those needing another transplant, with severe kidney issues (eGFR < 45), acute kidney injury stopping current treatments, congenital long QT syndrome, or high bilirubin levels (>100 umol/L) after their transplant.

Inclusion Criteria

Adults who have received a transplant at the University of Alberta.

Exclusion Criteria

I have congenital long QT syndrome.

I need a new organ transplant or multiple organ transplants.

I stopped taking calcineurin inhibitors due to acute kidney injury.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Envarsus or Prograf following liver transplantation to assess safety and efficacy

1 year

Regular visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment, including hospitalizations, complications, and survival

10 years

Annual visits for long-term monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Envarsus Oral Product
• Prograf

Trial Overview The study compares two drugs to prevent organ rejection after liver transplantation: standard Prograf and a new formulation called Envarsus. The goal is to see if Envarsus has fewer side effects and better clinical outcomes than Prograf.

How Is the Trial Designed?

Group I: Prograf (SOC) Experimental Treatment 1 Intervention

Prograf tablet Dose 0.10 - 0.15mg/Kg daily Frequency: 2 doses per day (dose above split in half for each dose)

Group II: Envarsus Active Control 1 Intervention

Envarsus tablet Dose 0.11 - 0.13 mg/Kg/day Frequency: once per day

Envarsus Oral Product is already approved in United States, European Union for the following indications:

Approved in United States as Envarsus XR for:

• Organ Transplant, Rejection Prophylaxis
• Organ Transplant, Rejection Reversal

Approved in European Union as Envarsus for:

• Liver transplantation
• Kidney transplantation

Who Is Running the Clinical Trial?

University of Alberta

Lead Sponsor

Trials

957

Recruited

437,000+

Published Research Related to This Trial

Extended release tacrolimus (Advagraf©, Astagraf XL©) offers a once-daily dosing option for kidney transplant recipients, potentially improving medication adherence while maintaining a similar safety and efficacy profile to the traditional twice-daily tacrolimus (Prograf©).

While extended release tacrolimus shows comparable pharmacokinetics to the standard formulation, it is not recommended for liver transplant patients due to an increased risk of mortality in female recipients, and there is limited data on its use in heart and lung transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of extended release tacrolimus in solid organ transplantation. Patel, N., Cook, A., Greenhalgh, E., et al.[2022]

Tacrolimus prolonged release (PR) is as effective as the immediate release (IR) formulation in kidney transplant recipients, showing noninferiority in phase III trials, while maintaining a similar tolerability profile.

Tacrolimus PR offers improved pharmacokinetic properties, including higher bioavailability and reduced concentration fluctuations, making it a promising option for both kidney and liver transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus prolonged release (Envarsus®): a review of its use in kidney and liver transplant recipients. Garnock-Jones, KP.[2022]

The EnGraft trial is comparing the bioavailability and effectiveness of Envarsus®, a once-daily tacrolimus formulation, against Advagraf™ in 268 liver transplant recipients, aiming to improve drug absorption and reduce toxicity.

Improved bioavailability of Envarsus® could lead to better clinical outcomes by achieving higher dose-normalized trough levels, potentially reducing renal dysfunction and neurotoxic side effects associated with tacrolimus treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EnGraft: a multicentre, open-label, randomised, two-arm, superiority study protocol to assess bioavailability and practicability of Envarsus® versus Advagraf™ in liver transplant recipients. Wöhl, DS., James, B., Götz, M., et al.[2023]

Once-daily formulations of tacrolimus (Advagraf® and Envarsus® XR) are not bioequivalent to the original twice-daily Prograf® formulation, meaning patients may need dosage adjustments when switching between these medications due to their narrow therapeutic index.

Intensive monitoring is essential after converting to once-daily tacrolimus, as the relationship between drug concentration and overall exposure can vary significantly across formulations, which could impact patient safety and treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients. Staatz, CE., Tett, SE.[2022]

Converting stable liver transplant patients from once-daily prolonged-release tacrolimus to once-daily extended-release tacrolimus is safe, with only two patients experiencing adverse effects that resolved after returning to the original medication.

This conversion not only reduced the mean daily cost of tacrolimus therapy from 5.54 to 4.11 Euros per patient but also required careful monitoring and dose adjustments to maintain effective serum levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients. Altieri, M., Delaval, G., Kimmoun, E., et al.[2018]

The extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) shows similar efficacy to the immediate-release version (Prograf®) in kidney transplant recipients, with no significant differences in patient/graft survival, acute rejection rates, or renal function across studies involving over 2,500 patients.

Advagraf® significantly improves medication adherence compared to Prograf®, which is crucial for long-term transplant success, and it has also been associated with favorable outcomes when combined with mTOR inhibitors, potentially reducing the risk of late-onset cytomegalovirus infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. Noble, J., Jouve, T., Rostaing, L., et al.[2021]

In a study involving 1391 liver transplant recipients treated with FK 506 (tacrolimus), the 4-year survival rate was significantly higher at 86.2% for pediatric patients and 71.4% for adults compared to 65.5% for both groups receiving cyclosporine.

FK 506 also demonstrated superior graft survival rates, with 77.0% in pediatric and 61.9% in adult patients, highlighting its effectiveness in reducing the need for retransplantation and improving outcomes related to rejection and complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression. Todo, S., Fung, JJ., Starzl, TE., et al.[2021]

Citations

1. envarsusxr.com envarsusxr.com/hcp/efficacy-safety

Clinical Data | ENVARSUS XR® (tacrolimus extended- ... At 1 year, recipients on ENVARSUS XR had a 9% lower risk of treatment failure vs those on Prograf® · At 2 years, recipients on ENVARSUS XR had a 17% lower risk ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03828058

Envarsus XL Immunosuppression Following Liver ... Our aim is to look at our prospective liver transplant group and see if once daily tacrolimus (Envarsus XR) results in improved renal function as well as ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4801790/

Overview of extended release tacrolimus in solid organ ... Extended release tacrolimus is not FDA approved for use in liver transplant recipients due to increased mortality rate in females in a post-hoc analysis. While ...

4. withpower.com withpower.com/trial/extended-release-tacrolimus-for-liver-transplant-complications-59e2d

Extended-Release Tacrolimus for Liver Transplant ... What data supports the effectiveness of the drug Envarsus XR for liver transplant complications? ... Envarsus has fewer side effects and better clinical outcomes ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2018/206406s007lbl.pdf

Envarsus XR - accessdata.fda.gov TPRI reported 450 and 241 total pregnancies in kidney and liver transplant recipients exposed to tacrolimus, respectively. The TPRI pregnancy outcomes are ...

6. envarsusxr.com envarsusxr.com/hcp/resources/consistency-case-study

Consistency Case Study | ENVARSUS XR® (tacrolimus ... De Novo kidney transplant patients: Most common adverse reactions (incidence ≥15%) reported with ENVARSUS XR are diarrhea, anemia, urinary tract infection, ...