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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two forms of Tacrolimus, a medication used to prevent organ rejection in liver transplant patients. It examines how each form affects liver and kidney function, as well as patients' experiences with side effects and adherence to their treatment plan. The study aims to determine if the once-daily version, Envarsus, is better or easier than the usual twice-daily Prograf. Ideal candidates for this trial include individuals who had a liver transplant over a year ago, currently take Prograf, and experience difficulties with side effects or maintaining their medication routine. As a Phase 4 trial, this research focuses on understanding how the already FDA-approved treatment can benefit more patients.

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 is the safety track record for these treatments?

Research shows that both Envarsus and Prograf are generally well-tolerated by liver transplant patients. Envarsus, a long-acting version of tacrolimus, has been found safe and effective for patients switching from other forms of tacrolimus. Its once-daily dosing can improve adherence to medication schedules. Although patients usually tolerate it well, tacrolimus can cause side effects that might affect long-term health.

Prograf, another form of tacrolimus, has been widely and safely used in liver transplant patients. Studies have shown high survival rates for patients using Prograf, similar to other tacrolimus forms. Like Envarsus, Prograf can cause side effects, including changes in kidney function and other health issues.

Both treatments have FDA approval for use in organ transplants, indicating a strong safety record. However, individual responses can vary, and some people might experience side effects. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about Envarsus for liver transplant patients because it offers a unique extended-release formulation. Unlike the standard of care, Prograf, which is typically taken twice daily, Envarsus allows for once-daily dosing, which can improve patient adherence and convenience. Additionally, Envarsus may lead to more stable blood levels of the medication, potentially reducing the risk of rejection and side effects. This could mean a smoother post-transplant experience for patients, which is why there's significant interest in its potential benefits.

What evidence suggests that this trial's treatments could be effective for liver transplant patients?

This trial will compare Prograf and Envarsus for liver transplant patients. Research has shown that both treatments are effective for these patients. Prograf, which participants in this trial may receive, is a common treatment that helps liver transplant patients live longer. Studies have found it effective and generally well-tolerated. Envarsus, another treatment option in this trial, is also safe and effective, offering similar protection for patients and their new liver. Both treatments are proven options for managing the body's immune response after a liver transplant. ^{1 3 4 6 7}

Who Is on the Research Team?

Nazia Selzner, MD

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

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

Multiorgan transplant

Severe cognitive impairment (as determined by clinical team)

Unwilling to consent

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34213506/

Evaluating the conversion to extended-release tacrolimus ... This observational study demonstrated that conversion of immediate-release tacrolimus to LCP-tac in liver transplant recipients was well ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05242315

Extended-Release Tacrolimus Following Liver ... Showing extended-release tacrolimus (Envarsus) is safe and efficacious will lead to broader use in the post-transplant setting. Use of this regimen leads to ...

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

Clinical Data | ENVARSUS XR® (tacrolimus extended- ... Patient and graft protection at 1 and 2 years. *Treatment failure was a composite endpoint of biopsy-proven acute rejection, graft failure, death, and loss to ...

4. pharmacy.unc.edu pharmacy.unc.edu/wp-content/uploads/sites/1043/2020/06/Kelly-Eric.pdf

Once Daily Extended Release Tacrolimus versus Twice ... The objective of this study was to compare the effectiveness and safety outcomes of once daily tacrolimus. ER tablets with twice daily IR tacrolimus capsules in ...

5. accp1.onlinelibrary.wiley.com accp1.onlinelibrary.wiley.com/doi/full/10.1002/cpdd.657

Tacrolimus ER Tablets vs Capsules in Liver Transplant The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10936969/

Modifying Tacrolimus-related Toxicity After Liver ... Tacrolimus is associated with a wide range of side effects with potential negative impact on long-term outcomes in liver transplant recipients.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9833930/

Improved Medication Adherence with the Use of Extended- ... Nonadherence to immunosuppression in liver transplant recipients (LTRs) leads to deterioration in health outcomes.