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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if switching from the medication Prograf to Envarsus XR (both forms of tacrolimus, an immunosuppressant drug) improves thinking and quality of life in individuals who have undergone a kidney transplant. Participants must have received their kidney transplant at least four weeks prior and be stable on their current medication. The trial seeks to understand if Envarsus XR can enhance cognitive function (mental sharpness) in these patients. It is intended for those stable on their current kidney transplant medication and not starting any new medications that might affect their treatment. As a Phase 4 trial, this research focuses on understanding how this already FDA-approved treatment can benefit more patients.

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 is the safety track record for these treatments?

Research has shown that Envarsus XR is generally safe for kidney transplant patients, with studies finding its safety comparable to other tacrolimus medications. In earlier trials, common side effects included diarrhea, anemia (a condition characterized by a deficiency of healthy red blood cells), and urinary tract infections, occurring in more than 15% of patients.

Envarsus XR has already received approval for use in some kidney transplant patients, indicating it is well-tolerated. This approval signifies that the FDA considers it safe for individuals who have undergone a kidney transplant.

Overall, the safety data for Envarsus XR suggests that while some side effects are common, they are similar to those seen with other kidney transplant medications. Evidence indicates that Envarsus XR is likely to be a safe option for participants in a clinical trial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Envarsus XR is unique because it offers a once-daily dosing option for kidney transplant patients, unlike the standard treatment, Prograf, which typically requires multiple doses a day. This extended-release formulation helps maintain steadier blood levels of the medication, potentially reducing side effects and improving patient adherence to their medication regimen. Researchers are excited about Envarsus XR's potential to simplify the treatment process and enhance the overall quality of life for those who have undergone kidney transplants.

What evidence suggests that switching from Prograf to Envarsus XR could improve cognitive function in kidney transplant patients?

Research has shown that Envarsus XR, a once-daily extended-release version of tacrolimus, works well for kidney transplant patients. Studies found that patients taking Envarsus XR had a 9% lower chance of treatment failure after one year compared to those taking Prograf. After two years, this risk was 17% lower. Envarsus XR is as safe and effective as other forms of tacrolimus. In this trial, all participants will switch from Prograf to Envarsus XR, which may help maintain kidney function and lead to better outcomes for transplant patients. ^{2 3 4 5 6}

Who Is on the Research Team?

Anthony Langone, MD

Principal Investigator

VUMC

Are You a Good Fit for This Trial?

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

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

Patients with a screening TAC-IR trough level of 3-9 ng/mL, measured between Day -7 to 0

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

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

Clinical Data | ENVARSUS XR® (tacrolimus extended- ... At 1 year, recipients on ENVARSUS XR had a 9% lower risk of treatment failure vs those on Prograf® · At 2 years, recipients on ENVARSUS XR had a 17% lower risk ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4801790/

Overview of extended release tacrolimus in solid organ ... Overall, extended release tacrolimus was shown to be safe and effective for nonsensitized kidney transplant recipients[27]. Yang et al[28] performed a 24-wk ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0272638615013451

Novel Once-Daily Extended-Release Tacrolimus Versus ... Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10944009/

Use of LCP-Tacrolimus (LCPT) in Kidney Transplantation LCPT (Envarsus XR®) is a common once-daily, extended-release oral tacrolimus formulation used in kidney transplantation.

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

206406Orig1s000 - accessdata.fda.gov Approval of Envarsus XR use in de novo kidney transplant patients is blocked by Astagraf XL exclusivity. 2. Background and Regulatory Issues.

6. envarsusxr.com envarsusxr.com/hcp/resources/consistency-case-study

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