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

Trial Summary

What is the purpose of this trial?

Medications used after transplant to prevent rejection are associated with many side effects. Tacrolimus side effects include kidney dysfunction; tremor, headaches, difficulty sleeping, change in sensation (legs), seizure, or confusion; high blood pressure; anemia, or low blood cell counts; diabetes; abnormal cholesterol and weight gain. The investigators want to use a new, approved, formulation of the standard medication (Envarsus) as they believe it may be associated with reduced side effects. The investigators would like to assess how safe it is to use this medication and how well it works in comparison to currently used formulations. The investigators will study if there are less side effects and will study clinical outcomes (including how well the liver does and if there is need for hospitalizations after transplant). The investigators hope that this information will improve the care provided to and outcomes in patients following liver transplant.

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 data supports the effectiveness of the drug Envarsus XR for liver transplant complications?

Research indicates that Envarsus XR, a once-daily extended-release formulation of tacrolimus, has improved bioavailability and reduced peak-to-trough fluctuations compared to other formulations. It has been shown to be non-inferior to twice-daily tacrolimus in kidney transplant patients, suggesting potential effectiveness in liver transplant recipients as well. ^{1 2 3 4 5}

Is extended-release tacrolimus safe for liver transplant patients?

Extended-release tacrolimus, like Envarsus, has a similar safety profile to the immediate-release version, but it is not recommended for liver transplant patients due to an increased risk of mortality in female recipients. ^{1 2 3 4 6}

How is the drug Envarsus different from other treatments for liver transplant complications?

Envarsus is a once-daily extended-release formulation of tacrolimus that uses MeltDose technology to improve drug bioavailability, leading to more consistent drug levels in the body and potentially better patient adherence compared to other formulations like Prograf, which is taken twice daily. ^{1 2 3 4 7}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

References

1. Turkey pubmed.ncbi.nlm.nih.gov

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients. [2018]

2. England 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. [2023]

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

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

4. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients. [2022]

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

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression. [2021]

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

Overview of extended release tacrolimus in solid organ transplantation. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021]