Envarsus XR for Kidney Transplant Patients

(OPERATOR Trial)

Overseen By Mohammed Sika, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Vanderbilt University Medical Center

Must be taking: Tacrolimus

Must not be taking: Prednisone, MMF, MPS

Disqualifiers: Other organ transplant, Dementia, 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: 16 weeks

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to assess cognitive outcome and quality of life in stable renal transplant patients treated with twice daily tacrolimus at baseline and after switching to Envarsus XL. The study is designed to see if switching patients from Tacrolimus to Envarsus treatment improves cognitive function.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot start any new medications that could interfere with tacrolimus blood levels. This includes certain prescription and over-the-counter medications, herbal or food supplements, and specific medications listed in the trial's appendix.

What data supports the effectiveness of the drug Envarsus XR for kidney transplant patients?

Research shows that Envarsus XR, a once-daily extended-release form of tacrolimus, is effective for kidney transplant patients. It has been found to have similar results in patient and graft survival compared to other tacrolimus formulations, with the added benefit of improved medication adherence. ^{1 2 3 4 5}

Is Envarsus XR safe for kidney transplant patients?

Envarsus XR, a once-daily formulation of tacrolimus, has been shown to be generally safe for kidney transplant patients. Studies indicate that it has similar safety outcomes compared to other tacrolimus formulations, with careful monitoring needed due to its narrow therapeutic index (small margin between effective and harmful doses). ^{1 2 4 5 6}

How is the drug Envarsus XR different from other treatments for kidney transplant patients?

Envarsus XR is a once-daily extended-release formulation of tacrolimus, which uses MeltDose™ technology to improve drug bioavailability, resulting in more consistent drug absorption and less fluctuation in drug levels compared to other formulations like Prograf and Advagraf. ^{1 2 3 4 5}

Research Team

Anthony Langone, MD

Principal Investigator

VUMC

Eligibility Criteria

This trial is for English-speaking adults aged 18-70 who've had a kidney transplant between 4 weeks and 10 years ago. They must be on a stable dose of Tacrolimus with specific blood levels, not planning to start interfering medications, and have no severe visual/hearing impairments or medical conditions that could affect participation.

Inclusion Criteria

Patients must be able to understand English and provide written informed consent

Males and females between 18 and 70 years of age

Patients receiving a stable dose (i.e., no dose adjustments) of TAC-IR for a minimum of 4-7 days at screening

Exclusion Criteria

Patients with an estimated glomerular filtration rate (eGFR) (MDRD4) < 25 mL/min at screening

Patients who have a history of any of the following, based on documentation of clinical conditions and concomitant medications in the medical records: Cognitive decline secondary to stroke, per Investigator discretion

Patients with an episode of biopsy-proven or suspected acute rejection that requires treatment within 3 months of screening

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are switched from Prograf to Envarsus and monitored for cognitive outcomes and quality of life

16 weeks

Regular visits for assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Envarsus XR
• Prograf

Trial Overview The study tests if switching from twice-daily Tacrolimus (Prograf) to Envarsus XR improves cognitive function in stable renal transplant patients. It assesses the impact of this medication change on their mental capabilities and quality of life.

Participant Groups

Group I: Change from Prograf to Envarsus Experimental Treatment 1 Intervention

All participants will be switched from Prograf to Envarsus

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?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

Veloxis Pharmaceuticals

Industry Sponsor

Trials

43

Recruited

3,200+

Findings from Research

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]

In a study of 638 kidney transplant recipients over 4 years, both tacrolimus formulations (Astagraf XL and Prograf) demonstrated similar patient and graft survival rates, with 93.2% and 91.2% survival respectively, compared to 91.7% for cyclosporine (CsA).

Patients on tacrolimus had a higher incidence of new-onset diabetes after transplantation (41.1% for Astagraf XL and 33.6% for Prograf) compared to 21.3% for CsA, but showed comparable renal function between the two tacrolimus formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients. Silva, HT., Yang, HC., Meier-Kriesche, HU., et al.[2021]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients. [2021]

3. 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]

4. Denmark pubmed.ncbi.nlm.nih.gov

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

5. 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]

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

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