Tacrolimus vs Envarsus for Neurotoxicity in Liver Transplant Patients

Overseen By David Taber, PharmD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Medical University of South Carolina

Must be taking: Immunosuppressants

Must not be taking: Tremor-inducing, Dopamine blockers

Disqualifiers: Pregnancy, HIV, Tremor conditions, 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: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines two medications used by liver transplant recipients to determine which one causes fewer nerve-related side effects. It compares the standard treatment, Tacrolimus (an immunosuppressant drug taken twice daily), with Envarsus (also an immunosuppressant drug taken once daily). The goal is to determine if Envarsus is gentler on the nerves than Tacrolimus. Individuals who have undergone a liver transplant in the past six months and can take oral medication may be suitable for this study. As a Phase 4 trial, it involves treatments already FDA-approved and proven effective, aiming to understand how they 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 you cannot participate if you are taking medications known to cause tremors or block dopamine.

What is the safety track record for these treatments?

Research has shown that Envarsus, a long-acting form of the drug tacrolimus, is safe for liver transplant patients. Taken once a day, it might help reduce some side effects. Some studies suggest it may cause fewer nerve-related side effects compared to the regular version of tacrolimus.

The regular version of tacrolimus, taken twice a day, is a well-known treatment that has helped many transplant patients but can sometimes cause nerve problems. Researchers aim to compare these two forms.

Both Envarsus and regular tacrolimus have been used safely in patients, but each can have different side effects. The study seeks to determine if Envarsus is gentler on the nerves for liver transplant recipients. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about Envarsus because it offers a unique once-daily dosing option, which can simplify medication routines for liver transplant patients. Unlike standard tacrolimus treatments that require multiple doses throughout the day, Envarsus uses a special extended-release formulation to maintain stable drug levels with just one dose a day. This not only improves convenience but may also help reduce the risk of neurotoxicity, which is a common side effect associated with higher peaks and troughs in drug levels.

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

Research has shown that Envarsus, a long-acting form of the drug tacrolimus, works well for liver transplant patients and is just as effective as the regular form of tacrolimus, which is commonly used. In this trial, participants will receive either Envarsus daily or Tacrolimus immediate release twice daily. Envarsus offers benefits such as better absorption and more consistent blood levels, potentially leading to fewer side effects, particularly those affecting the nervous system, like shaking or confusion. By maintaining a steady drug level in the body, Envarsus may cause fewer side effects, making it a better choice for some patients who experience side effects from the regular form of tacrolimus. ^{1 2 3 4 6}

Who Is on the Research Team?

Derek Dubay, MD

Principal Investigator

Medical University of South Carolina

Are You a Good Fit for This Trial?

This trial is for adults over 18 who've had a liver or liver/kidney transplant in the last 6 months. They must understand and agree to the study's terms. It's not for pregnant or nursing individuals, HIV positive patients, those unable to take oral meds, recently used other investigational drugs, have certain rejection issues post-transplant, tremor-causing conditions, or are on tremor-inducing meds.

Inclusion Criteria

Patients must be capable of understanding the purposes and risks of the study and have the ability to give written informed consent and be willing to participate and comply with the study

Exclusion Criteria

Pregnant or nursing females or males with a pregnant female partner

You have tested positive for HIV.

You cannot handle taking pills or tablets.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Envarsus once daily or Tacrolimus immediate release twice daily for 6 months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Envarsus
• Tacrolimus Immediate release

Trial Overview The study compares two immunosuppressant medications: standard Tacrolimus (taken twice daily) versus Envarsus (once daily), focusing on their neurological side effects in liver transplant patients. The hypothesis suggests that Envarsus may lead to fewer neurologic side effects than Tacrolimus.

How Is the Trial Designed?

Group I: Arm 2: Intervention Experimental Treatment 1 Intervention

Envarsus daily for 6 months.

Group II: Arm 1: Control Active Control 1 Intervention

Tacrolimus immediate release twice daily for 6 months

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?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

Veloxis Pharmaceuticals

Industry Sponsor

Trials

43

Recruited

3,200+

Published Research Related to This Trial

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]

In a study of 30 kidney transplant patients transitioning from immediate-release to extended-release tacrolimus, the median weight-based dose that achieved therapeutic levels was approximately 0.158 mg/kg/day, which aligns with the manufacturer's recommendation of 80% of the original dose.

However, the study found significant variability in dosing effectiveness among patients, indicating that a weight-based dosing strategy alone may not reliably predict therapeutic levels for all individuals, particularly across different racial backgrounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Weight-Based Dose During Transition From Immediate-Release to Extended-Release Tacrolimus in Kidney Transplant Recipients. Magid, M., Sanoff, S., Lee, HJ., 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05242315

Extended-Release Tacrolimus Following Liver ... Tacrolimus side effects include kidney dysfunction; tremor, headaches, difficulty sleeping, change in sensation (legs), seizure, or confusion; high blood ...

2. 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.

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

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

4. withpower.com withpower.com/trial/phase-4-neurotoxicity-syndromes-2020-f02cd

Tacrolimus vs Envarsus for Neurotoxicity in Liver ... It has similar effectiveness and tolerability to the immediate-release version, with the added benefit of improved drug absorption and more stable blood levels.

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. clinicaltrials.gov clinicaltrials.gov/study/NCT03823768

Envarsus Neurotoxicity Burden in Liver Transplant Patients We hypothesize that Envarsus will show a lower rate of neurologic side effects than immediate release tacrolimus.