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

Trial Summary

What is the purpose of this trial?

This is a Phase II/III, Single-center, Prospective, Open-label, Single Arm Study of 20 Simultaneous Kidney Pancreas recipients who received a transplant at least 3 months, but no more than 5 years prior, with a history of tremors following transplantation.

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.

What data supports the effectiveness of the drug Envarsus XR for tremors post-transplant?

Envarsus XR, a once-daily formulation of tacrolimus, has shown improved drug absorption and less variability in blood levels compared to other tacrolimus formulations, which can help with medication adherence and potentially reduce the risk of organ rejection in transplant patients. ^{1 2 3 4 5}

Is Envarsus XR safe for humans?

Envarsus XR, a once-daily formulation of tacrolimus, has been studied in various transplant patients and is generally considered safe, but it requires careful monitoring due to its narrow therapeutic index (small margin between effective and harmful doses). It has been shown to have improved drug absorption and less variability in blood levels compared to other formulations, which can help reduce side effects and improve safety. ^{1 2 3 4 6}

How is the drug Envarsus XR different from other treatments for tremors post-transplant?

Envarsus XR is unique because it is a once-daily, extended-release formulation of tacrolimus, which uses MeltDose technology to improve drug absorption and reduce fluctuations in drug levels, potentially leading to better adherence and fewer side effects compared to other tacrolimus formulations. ^{1 2 3 4 7}

Research Team

Jon S Odorico, MD

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

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.

I am between 18 and 70 years old.

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

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

Treatment Details

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.

Participant Groups

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+

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 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]

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 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 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]

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]

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. Denmark pubmed.ncbi.nlm.nih.gov

Envarsus XR® pharmacokinetics in adolescents post-kidney transplantation - A pilot study. [2023]

3. 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]

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

Evaluation of Weight-Based Dose During Transition From Immediate-Release to Extended-Release Tacrolimus in Kidney Transplant Recipients. [2023]

5. England pubmed.ncbi.nlm.nih.gov

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

6. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

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