Envarsus XR for Tremors Post-Transplant

Overseen By Jon S Odorico, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of Wisconsin, Madison

Must be taking: Immediate-release tacrolimus

Must not be taking: Extended-release tacrolimus

Disqualifiers: Tremors prior, Solitary pancreas, 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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the drug Envarsus XR (a form of tacrolimus) can reduce tremors in individuals who have undergone kidney and pancreas transplants. It targets those who received their transplant between 3 months and 5 years ago and have experienced tremors since. Participants should have a history of diabetes that necessitated a transplant and must be stable without needing additional insulin. The study involves taking Envarsus XR once daily for six months. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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

The trial does not specify if you need to stop taking your current medications, but you must currently be taking Immediate-Release (IR) tacrolimus to participate.

Is there any evidence suggesting that Envarsus XR is likely to be safe for humans?

Research has shown that Envarsus XR, a long-acting form of the drug tacrolimus, is generally well-tolerated by patients. Studies have found that it can help control hand tremors in kidney transplant recipients, which is encouraging for those with similar conditions. The FDA has already approved Envarsus XR for kidney transplant patients, indicating a certain level of safety.

However, like any medication, it can have side effects. Some individuals might experience tremors due to tacrolimus, the main ingredient in Envarsus XR. The risk of tremors can vary depending on the type of transplant, with kidney and bone marrow transplant patients having a higher risk than liver transplant patients.

Overall, the safety of Envarsus XR is considered acceptable, but individual experiences can differ. Discussing any concerns with a doctor before joining a clinical trial is always advisable. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for post-transplant tremors involve medications like beta-blockers or anticonvulsants, which can have a range of side effects and often require multiple doses throughout the day. Envarsus XR is unique because it offers an extended-release formulation that is taken just once daily, potentially improving patient adherence and convenience. Additionally, Envarsus XR is designed to provide more stable blood levels of the active ingredient, tacrolimus, which may lead to better management of tremors with fewer side effects. Researchers are excited because this could mean a more effective and simpler treatment option for those dealing with tremors after a transplant.

What evidence suggests that Envarsus XR might be an effective treatment for tremors post-transplant?

Research has shown that Envarsus XR, a long-acting form of tacrolimus, may help reduce hand tremors in kidney transplant patients. Studies have found that switching to Envarsus XR leads to noticeable improvements in tremors compared to other forms of tacrolimus. This medication releases steadily over time, potentially managing symptoms more effectively. Reports indicate that patients experience a better quality of life after switching, suggesting it as a viable option for managing tremors post-transplant. The treatment has already proven effective for kidney transplant patients, supporting its use in this context. Participants in this trial will receive Envarsus XR to evaluate its effectiveness in reducing post-transplant tremors. ^{1 2 3 4 6}

Who Is on the Research Team?

Jon S Odorico, MD

Principal Investigator

University of Wisconsin, Madison

Are You a Good Fit for This Trial?

This trial is for adults aged 18-70 who had a simultaneous kidney and pancreas transplant between 3 months to 5 years ago, have stable organ function without diabetes medication, and developed tremors post-transplant. It's not for those with previous tremors, other organ transplants, specific immune system antibodies or on extended-release tacrolimus.

Inclusion Criteria

You have experienced shaking (tremors) after receiving an organ transplant in the past.

My pancreas transplant is working well without needing insulin or diabetes pills.

My kidney transplant is functioning well.

Exclusion Criteria

Presence of Donor Specific Antibodies

I have received a pancreas transplant only.

I am currently on a long-acting tacrolimus medication plan.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Envarsus XR (extended release) orally, once-daily, for 6 months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Envarsus XR

Trial Overview The study tests Envarsus XR in patients who received a simultaneous pancreas-kidney transplant. It aims to see if this drug can manage tremors that started after the surgery. Participants must currently be taking Immediate-Release tacrolimus and will switch to Envarsus XR.

How Is the Trial Designed?

Group I: Envarsus XR Experimental Treatment 1 Intervention

Envarsus XR (extended release) will be administered orally, once-daily, for 6 months.

Envarsus XR 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 of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

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]

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]

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]

The pharmacokinetic profile of Envarsus XR® (LCPT) in three adolescent renal transplant recipients showed similar characteristics to adults, indicating that it may be a suitable option for this age group.

Adolescents on LCPT had a higher area under the curve (AUC) and a longer time to reach peak concentration (Tmax) compared to pediatric patients on other tacrolimus formulations, suggesting improved drug exposure and potentially more stable drug levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Envarsus XR® pharmacokinetics in adolescents post-kidney transplantation - A pilot study. ElChaki, R., Ettenger, R., Lee, S., et al.[2023]

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]

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]

Citations

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

Clinical Data | ENVARSUS XR® (tacrolimus extended- ... ENVARSUS XR has been studied across multiple kidney transplant recipient types, including de novo patients, stable patients converting from other tacrolimus ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4755036/

Switching STudy of Kidney TRansplant PAtients with ... Results suggest LCPT is associated with clinically meaningful improvement of hand tremor and may be an alternative management approach in lieu of further dose ...

3. envarsusxr.com envarsusxr.com/hcp/resources/control-case-study

Control Case Study | ENVARSUS XR® (tacrolimus ... This case study highlights the first days of Daryl's post-transplant journey to target tacrolimus levels as quickly as possible.

4. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2015/206406Orig1s000SumR.pdf

206406Orig1s000 - accessdata.fda.gov For clinical and pharmacokinetic data, Veloxis submitted results of multiple. Phase 1, Phase 2 and Phase 3 studies conducted using Envarsus XR ( ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0041134524000800

Conversion From Immediate-Release to Prolonged ... Tremor significantly diminishes the quality of life in transplant patients [8,9] and contributes to medication noncompliance [8,10,11]. A prolonged-release ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0955470X23000691

The association between tacrolimus exposure and tremor ... They found a greater risk of Tac-induced tremor in kidney transplant recipients and bone marrow recipients than in liver transplant recipients; however, in five ...