Envarsus XR for Tremors Post-Transplant

Recruiting in Palo Alto (17 mi)

Overseen by Jon S Odorico, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

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

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This is a Phase II/III, Single-center, Prospective, Open-label, Single Arm Study of 30 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.

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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.

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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.

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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.

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Wisconsin Madison, WI

Who Is Running the Clinical Trial?

University of Wisconsin, Madison Lead Sponsor

Veloxis Pharmaceuticals Industry Sponsor

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] After organ transplant, strategies to simplify the therapeutic regimen may improve adherence and prevent rejection and/or graft loss. The aim of the present study was to evaluate the safety of conversion from once-daily prolonged-release tacrolimus (Advagraf; Astellas Pharma Europe Limited, Middlesex, UK) to once-daily extended-release tacrolimus (Envarsus; Chiesi SAS, Nanterre, France) in stable adult liver transplant recipients.

2. Denmark pubmed.ncbi.nlm.nih.gov

Envarsus XR® pharmacokinetics in adolescents post-kidney transplantation - A pilot study. [2023] Envarsus XR® (LCPT), a once daily dosage formulation of tacrolimus, is an FDA-approved medication in adult renal transplant recipients (RTRs). There are limited data on its pharmacokinetics (PK) in adolescent RTRs. We report here the PK profile of LCPT in adolescent RTRs.

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] Graft rejection and chronic CNI toxicity remain obstacles to organ transplant success. Current formulations of tacrolimus, such as Prograf® and Advagraf™, exhibit limitations in terms of pharmacokinetics and tolerability, related in part to suboptimal bioavailability. As dosing non-compliance can result in graft rejection, the once daily formulation of tacrolimus, Advagraf™, was developed (vs 2x/day Prograf®). Benefits of Advagraf™ are counterbalanced by delayed achievement of therapeutic trough levels and need for up to 50% higher doses to maintain Prograf®-equivalent troughs. Envarsus® is also a prolonged-release once-daily tacrolimus formulation, developed using MeltDose™ drug-delivery technology to increase drug bioavailability; improved bioavailability results in low patient drug absorption variability and less pronounced peak-to-trough fluctuations. In phase III de novo kidney transplant studies, Envarsus® proved non-inferior to twice-daily tacrolimus; however, no phase IV studies show superiority of Envarsus® vs Advagraf™ in de novo liver transplant (LTx) recipients.

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] Manufacturer recommendations for conversion from immediate-release to extended-release tacrolimus, Envarsus XR®, suggests 80% of the total daily dose of the immediate-release formulation. This conversion has not consistently achieved therapeutic levels in the kidney transplant population.

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

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021] Cornerstone immunosuppressive therapy currently relies on immediate-release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf®/Astagraf XL®, Astellas company) and a long-lasting formulation (Envarsus®, Veloxis company). Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) used in conjunction with or without an induction therapy (i.e., basiliximab) in de novo kidney-transplant recipients. To achieve this, we searched for suitable articles through PubMed. Expert commentary: Phases-III and -IV studies comparing Advagraf®/Astagraf XL® to Prograf® in association with mycophenolate mofetil (more than 2,500 patients) have demonstrated overall similar results with regards to patient/graft survival, biopsy-proven acute-rejection rate, and renal function (p > 0.05). A randomized controlled study in maintenance kidney transplant patients has shown (using electronic monitoring) that, as compared to Prograf®, Advagraf® significantly improved adherence to medication. Other studies report that Advagraf®-treated patients receiving a mTOR-inhibitor agent (sirolimus or everolimus) instead of MMF: this was associated with good allograft outcome, and might also prevent late-onset cytomegalovirus infection. Advagraf®-based immunosuppression given to de novo kidney-transplant recipients, with or without an induction therapy, provided excellent results compared to Prograf®; it also increased patients' adherence to treatment.

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

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients. [2022] Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf(®), a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf(®) and Envarsus(®) XR) and various generic versions of Prograf(®) are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf(®), Advagraf(®) and Envarsus(®) XR are not bioequivalent [in terms of the area under the concentration-time curve from 0 to 24 h (AUC0-24) or the minimum concentration (C min)]. Patients may require a daily dosage increase if converted from Prograf(®) to Advagraf(®), while a daily dosage reduction appears necessary for conversion from Prograf(®) to Envarsus(®) XR. Prograf(®) itself, or generic immediate-release tacrolimus, can be administered in a once-daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC0-24 and C min is variable and not strong for all three formulations, indicating that trough measurements may not always give a good indication of overall drug exposure. Further investigation is required into whether the prolonged-release formulations have reduced within-subject pharmacokinetic variability, which would be a distinct advantage. Whether the effects of factors that influence tacrolimus absorption and pre-systemic metabolism (patient genotype status; gastrointestinal disease and disorders) and drug interactions differ across the formulations needs to be further elucidated. Most pharmacokinetic comparison studies to date have involved relatively stable patients, and many have been sponsored by the pharmaceutical companies manufacturing the new formulations. Larger randomized, controlled trials are needed in different transplant populations to determine whether there are differences in efficacy and toxicity across the formulations and whether formulation conversion is worthwhile in the longer term. While it has been suggested that once-daily administration of tacrolimus may improve patient compliance, further studies are required to demonstrate this. Mistakenly interchanging different tacrolimus formulations can lead to serious patient harm. Once-daily tacrolimus is now available as an alternative to twice-daily tacrolimus and can be used de novo in solid-organ transplant recipients or as a different formulation for existing patients, with appropriate dosage modifications. Clinicians need to be fully aware of pharmacokinetic and possible outcome differences across the different formulations of tacrolimus.

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

Tacrolimus prolonged release (Envarsus®): a review of its use in kidney and liver transplant recipients. [2022] Tacrolimus prolonged release (Envarsus®; henceforth referred to as tacrolimus PR) is a new, once-daily, prolonged-release tacrolimus formulation, utilizing a drug delivery technology designed to enhance the bioavailability of drugs with low water solubility by creating a solid solution of the drug. This article reviews the pharmacological properties of tacrolimus PR and its clinical efficacy and tolerability in adult kidney and liver transplant recipients. In phase III trials, tacrolimus PR was noninferior to tacrolimus immediate release (IR; twice daily) in both de novo and stable, previously treated kidney transplant recipients, and had a similar tolerability profile. Preliminary efficacy data from phase II trials in de novo and stable, previously treated liver transplant recipients imply that tacrolimus PR is effective in these patient groups; however, more data would be of interest. Pharmacokinetic analyses demonstrated that tacrolimus PR is associated with a higher bioavailability, reduced peak-trough concentration fluctuation ratio, lower mean values for percentage degree of fluctuation and percentage degree of swing, and a longer time to maximum concentration than tacrolimus IR. Tacrolimus PR is a promising addition to the treatment options available for kidney and liver transplant recipients.