Envarsus XR vs Tacrolimus for Kidney Failure

Recruiting at 1 trial location

Overseen By Deepa Valvi, DrPH

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Roberto Gedaly

Must not be taking: Blood thinners, Glucocorticoids

Disqualifiers: Previous transplant, Cancer, HIV, 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: 10

Duration: 6 months

78 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, Envarsus XR and tacrolimus, to manage kidney failure in patients awaiting a kidney transplant. Researchers aim to determine if Envarsus XR, taken once daily, is as effective as tacrolimus, taken twice daily. The study seeks individuals with end-stage kidney disease who are on the list for their first kidney transplant. Participants should be comfortable with the study guidelines and able to consent in English. As a Phase 2, Phase 3 trial, this research evaluates the treatment's effectiveness in a smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in kidney transplant care.

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

The trial does not specify if you need to stop taking your current medications, but it excludes those who are on chronic blood thinners or anticoagulation medication. It's best to discuss your specific medications with the trial coordinators.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Envarsus XR and tacrolimus are generally safe for people with kidney transplants. Envarsus XR has been tested in various groups, including those new to transplant drugs and those switching from other tacrolimus forms. The safety results, such as side effects and serious conditions, were similar for users of Envarsus XR and other tacrolimus types.

For tacrolimus, studies have also confirmed its safety, with no unexpected issues reported over two years in kidney transplant patients. Common side effects for both treatments include diarrhea, low red blood cell count (anemia), and urinary tract infections.

Both treatments are already used in transplant patients and have a strong safety record. While side effects can occur, they are usually manageable and expected with these treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Envarsus XR for kidney failure because it offers a once-daily dosing regimen, which is more convenient compared to the twice-daily dosing required by Tacrolimus, the standard treatment. Envarsus XR uses an extended-release formulation, potentially leading to more stable drug levels in the body and reducing peaks and troughs that can cause side effects. This improved consistency in drug delivery might also enhance patient adherence and overall outcomes.

What evidence suggests that this trial's treatments could be effective for kidney failure?

This trial will compare Envarsus XR with Tacrolimus for kidney transplant patients. Research has shown that Envarsus XR, a long-acting version of tacrolimus, may benefit these patients. Specifically, after one year, patients using Envarsus XR had a 9% lower chance of treatment failure compared to those using the regular form of tacrolimus, Prograf. This advantage increased to a 17% lower risk after two years. Envarsus XR releases the medication more steadily, helping maintain consistent blood levels.

Tacrolimus, the standard treatment in this trial, also delivers strong results. Studies report high survival rates for both patients and their transplanted kidneys, with figures like 98.6% and 96.7%, respectively, after one year. Both treatments are effective, but Envarsus XR might offer a smoother experience with less risk of sudden drops in medication levels. ^{3 6 7 8 9}

Who Is on the Research Team?

Roberto Gedaly, MD

Principal Investigator

University of Kentucky

Are You a Good Fit for This Trial?

This trial is for English-speaking adults with end-stage renal disease who are listed for their first kidney transplant. They must be willing to use two forms of contraception if they're women of childbearing potential. People can't join if they've had previous transplants, certain infections or cancers, recent blood transfusions, or are on specific medications like anticoagulants.

Inclusion Criteria

Willing to participate in the study and comply with study requirements as evidenced by signed IRB-approved informed consent

I am using two forms of birth control during and for a year after the study.

I am on the waiting list for a kidney transplant due to end stage renal disease.

Exclusion Criteria

Are pregnant or breastfeeding

I am currently taking blood thinners.

I have had an organ, tissue, or cell transplant in the past.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants are randomized to receive either Envarsus XR or Tacrolimus starting on post-op day 1

6 months

9 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in GFR and blood immunologic markers

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Envarsus XR
• Tacrolimus

Trial Overview The study compares Envarsus XR®, a once-daily tacrolimus formulation, with the standard twice-daily tacrolimus in patients awaiting a primary solitary kidney transplant. It's an open-label and randomized trial but doesn't include the actual transplant surgery as part of the study.

How Is the Trial Designed?

Group I: Envarsus XR Experimental Treatment 1 Intervention

0.07-0.14 mg/kg/day every morning orally

Group II: Tacrolimus Active Control 1 Intervention

0.1 - 0.2 mg/kg/day in 2 divided doses every 12 hours orally

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?

Roberto Gedaly

Lead Sponsor

Trials

2

Recruited

90+

Veloxis Pharmaceuticals

Industry Sponsor

Trials

43

Recruited

3,200+

Published Research Related to This Trial

HX575, a biosimilar to epoetin alfa, was found to be clinically equivalent to the reference drug in maintaining hemoglobin levels in dialysis patients with chronic kidney disease-related anemia, based on a study involving multiple centers and a significant number of participants.

The safety profiles of HX575 and the reference epoetin alfa were similar, with no development of clinically relevant antibodies, indicating that HX575 is a safe alternative for treating anemia in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comparison of the Safety and Efficacy of HX575 (Epoetin Alfa Proposed Biosimilar) with Epoetin Alfa in Patients with End-Stage Renal Disease. Weir, MR., Pergola, PE., Agarwal, R., et al.[2018]

In a study of 102,240 patients with chronic kidney disease or chemotherapy-related anemia, 15.5% switched between erythropoiesis-stimulating agents (ESAs) within the first year, indicating a notable frequency of switching, particularly towards originator products rather than biosimilars.

Factors such as the number of cumulative transfusions and the severity of chronic kidney disease were identified as predictors for switching ESAs, suggesting that patient treatment needs may influence the choice of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study. Ingrasciotta, Y., Belleudi, V., Trotta, F., et al.[2020]

PROCRIT, an exogenous form of erythropoietin, is effective for treating anemia in predialysis patients and HIV-positive patients receiving AZT, providing a therapeutic option for these groups.

The choice between PROCRIT and its identical counterpart, Epogen, may depend on cost and the need for frequent clinic visits for predialysis patients, who require injections two to three times a week.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epoetin alfa for predialysis and AZT-treated HIV-positive patients. Holechek, MJ.[2016]

In a pooled analysis of 408 patients with non-dialysis-dependent chronic kidney disease, those who were poor responders to continuous erythropoietin-receptor activator (CERA) had significantly lower hemoglobin levels and eGFRs, leading to worse renal survival outcomes.

The study found that 36.3% of poor responders experienced renal events compared to 23.0% of good responders, with a significant difference in renal survival rates, suggesting that hyporesponsiveness to CERA is linked to poorer renal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between responsiveness to methoxy polyethylene glycol-epoetin beta and renal survival in patients with non-dialysis-dependent chronic kidney disease: A pooled analysis of individual patient-level data from clinical trials. Tsuruya, K., Uemura, Y., Hirakata, H., et al.[2018]

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 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 63 patients with chronic kidney disease, those treated with continuous erythropoietin receptor activator (CERA) maintained significantly higher hemoglobin levels and reticulocyte counts compared to those treated with darbepoetin-α (DA) at the time of dialysis initiation.

CERA demonstrated a more stable effect on hemoglobin maintenance over the 3 months before dialysis, suggesting it may be a more effective treatment option for managing anemia in CKD patients compared to DA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comparative Study of the Hemoglobin-Maintaining Effects Between Epoetin-β Pegol and Darbepoetin-α in Patients with Chronic Kidney Disease During 3 Months Before Dialysis Initiation. Oka, S., Obata, Y., Torigoe, K., 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]

In a study comparing Advagraf (AVF) and Prograf (PGF) in 30 de novo kidney transplant patients, it was found that while both medications had similar overall exposure to tacrolimus, patients on AVF required higher median doses (9.8 mg/d) compared to those on PGF (7.9 mg/d) to achieve targeted drug levels in the early post-transplant period.

Despite the higher doses needed for AVF, both formulations showed similar efficacy in terms of drug exposure, suggesting that monitoring should include assessing area under the curve (AUC) or peak levels for patients not reaching target levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic drug monitoring in de novo kidney transplant receiving the modified-release once-daily tacrolimus. Jelassi, ML., Lefeuvre, S., Karras, A., et al.[2013]

In a study of 199 stable kidney transplant recipients, converting from the twice-daily tacrolimus formulation (Prograf) to the once-daily formulation (Advagraf) resulted in a significant reduction in tacrolimus trough levels by an average of 13.5% after one month, indicating a change in drug absorption or metabolism.

Despite the potential benefits of improved adherence with Advagraf, 17% of patients discontinued treatment and 1% experienced acute rejection, suggesting that conversion should be carefully considered on an individual basis to avoid increasing the risk of allograft rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conversion to prolonged release tacrolimus formulation in stable kidney transplant recipients. Wu, SW., Tsai, HC., Tsai, PY., et al.[2018]

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]

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

Control 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, ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10582328/

The effect of tacrolimus conversion from immediate- to ... Renal function and patient-reported outcomes in stable kidney transplant patients following conversion from twice-daily immediate-release ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04838288

Cognitive Outcomes in Stable Renal Transplant Patients ... In stable kidney transplant patients, ENVARSUS XR pharmacokinetics are characterized by a steadier and more consistent concentration time profile over 24 hours, ...

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/convenience-case-study

Convenience Case Study In the MELT trial, efficacy failure events and safety outcomes at 12 months were consistent between patients who switched to ENVARSUS XR and patients who ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03511560

Envarsus on the Effect of Total Tacrolimus Dose/Trough ... It will examine kidney function between the two groups using estimated glomerular filtration rate (eGFR) and also examine one-year kidney outcomes, including ...

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

Consistency Case Study | ENVARSUS XR® (tacrolimus ... ENVARSUS XR is indicated for the prophylaxis of organ rejection in de novo kidney transplant patients in combination with other immunosuppressants. ENVARSUS XR ...

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

Novel Once-Daily Extended-Release Tacrolimus Versus ... Safety end points included adverse events, serious adverse events, new-onset diabetes, kidney function, opportunistic infections, and malignancies.