Prograf vs Envarsus for Liver Transplant Patients

Overseen By Erin Winter, BSC

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University Health Network, Toronto

Must be taking: Prograf

Disqualifiers: Multiorgan transplant, Severe illness, 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: 48 weeks

40 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it involves either staying on your current dose of Prograf or switching to Envarsus. It seems you will continue with one of these medications during the trial.

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

Envarsus, a once-daily extended-release form of tacrolimus, has been shown to improve drug bioavailability and reduce variability in drug absorption, which can help maintain stable drug levels and potentially improve adherence in liver transplant patients. ^{1 2 3 4 5}

Is tacrolimus safe for liver transplant patients?

Tacrolimus, used in various formulations like Prograf and Envarsus, is generally safe for liver transplant patients, with similar safety profiles across different versions. Studies show that adverse events are comparable between once-daily and twice-daily formulations, and it is well tolerated in patients. ^{3 4 5 6 7}

How does the drug Envarsus differ from other treatments for liver transplant patients?

Envarsus is a unique formulation of tacrolimus that offers a once-daily dosing schedule, which can improve medication adherence compared to the more frequent dosing required by other tacrolimus formulations like Prograf. This extended-release form may also provide more stable blood levels, potentially reducing side effects and improving overall management of liver transplant patients. ^{8 9 10 11 12}

What is the purpose of this trial?

Prograf and Envarsus are two different formulations of Tacrolimus which is used as an immunosuppressant in liver transplant (LT) patients. Prograf is currently used as part of the standard immunosuppression regimen for LT recipients at UHN. This study will compare the use of Prograf and Envarsus and their effects on liver and renal function, trough tacrolimus levels, drug-related adverse effects, and patient adherence. Trial design is a pilot randomized trial. The study aims to recruit 40 patients from UHN's LT program and they will be randomized 1:1 to either stay on their current dose of Prograf or be converted to a once-daily equivalent dose of Envarsus. Both groups of patients will be followed for 48 weeks. This study will compare the change from baseline to week 48 in liver and renal function, tacrolimus-related side effects and patient reported outcomes between the two study groups.

Research Team

Nazia Selzner, MD

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

This trial is for adults over 18 who had a liver transplant more than a year ago, are on Prograf immunosuppression with specific blood test levels, stable liver and kidney function, no recent rejection episodes, and issues like tremors or sleep problems possibly due to their current medication.

Inclusion Criteria

I am on Prograf medication with specific blood level targets.

It has been over a year since my liver transplant.

I haven't had a rejection episode in the last 6 months.

Exclusion Criteria

Severe cognitive impairment (as determined by clinical team)

Unwilling to consent

Multiorgan transplant

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to either continue Prograf or switch to Envarsus and are monitored for liver and renal function, tacrolimus levels, and side effects

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Envarsus
• Prograf

Trial Overview The study compares two drugs used to prevent organ rejection after liver transplants: Prograf and Envarsus. Participants will either continue taking Prograf or switch to an equivalent dose of Envarsus once daily. They'll be monitored for 48 weeks to see effects on liver/renal function and drug side effects.

Participant Groups

Group I: Post-liver transplant patients receiving Prograf Active Control 1 Intervention

Group II: Post-liver transplant patients receiving Envarsus Active Control 1 Intervention

Envarsus is already approved in United States for the following indications:

Approved in United States as Envarsus XR for:

• Prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Paladin Labs Inc.

Collaborator

Trials

4

Recruited

360+

Findings from Research

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]

In a case study of a 42-year-old male liver transplant recipient, the addition of deoxyschisandrin significantly increased the blood concentration of tacrolimus (Tac) from 2.3 ng/mL to 17.7 ng/mL within three days, indicating a potential interaction that enhances Tac levels.

This case highlights the importance of closely monitoring tacrolimus levels when deoxyschisandrin is used concurrently, as it may lead to increased risk of toxicity and necessitate adjustments in immunosuppressive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of deoxyschisandrin on blood tacrolimus levels: a case report. Jiang, W., Wang, X., Kong, L.[2017]

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]

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]

References

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

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

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

The effect of deoxyschisandrin on blood tacrolimus levels: a case report. [2017]

3. 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]

4. 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]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. [2023]

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

Comparison of the long-term efficacy and safety of generic tacrolimus, Tacrobell, with Prograf in liver transplant recipients. [2022]

8. Australia pubmed.ncbi.nlm.nih.gov

Bone and renal safety profile at 72 weeks after switching to tenofovir alafenamide in chronic hepatitis B patients. [2022]

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

High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review. [2023]

10. Denmark pubmed.ncbi.nlm.nih.gov

Safety and efficacy of tenofovir alafenamide in liver transplant recipients: A single center experience. [2021]

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

Entecavir versus tenofovir on the recurrence of hepatitis B-related HCC after liver transplantation: A multicenter observational study. [2023]

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

Renal Outcomes With Tenofovir Alafenamide in Liver Transplant Recipients. [2023]