Once-Daily vs Twice-Daily Tacrolimus for Kidney Transplant Recipients

(SIMPLE Trial)

No longer recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Mayo Clinic

Must be taking: Tacrolimus

Must not be taking: Azathioprine, mTOR inhibitors, Belatacept

Disqualifiers: Professional care, Investigational immunosuppression

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: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if taking tacrolimus, a medication used after kidney transplants, once a day is more effective than taking it twice a day. Researchers are examining whether the once-daily version, Envarsus XR, leads to fewer side effects, better medication adherence, and improved quality of life. The trial includes adults who have received a kidney transplant and can follow study procedures. Participants will take either the once-daily or twice-daily version of the medication to compare outcomes. As a Phase 4 trial, this study involves an FDA-approved treatment, helping to understand its benefits for a broader patient population.

Do I have to stop taking my current medications for the trial?

The trial requires that you do not take certain medications like azathioprine, mTOR inhibitors (such as sirolimus or everolimus), or belatacept. If you are on these, you would need to stop them to participate.

What is the safety track record for these treatments?

Research shows that both Envarsus XR and immediate-release tacrolimus are generally well-tolerated by patients.

For Envarsus XR, studies have found that common side effects, affecting more than 15% of patients, include diarrhea, low red blood cell count (anemia), and urinary tract infections. These side effects are similar to those seen with other forms of tacrolimus and are expected.

Immediate-release tacrolimus has a similar safety profile. Research indicates it has significantly improved outcomes for kidney transplant patients and remains an important part of treatment. Like Envarsus XR, it has common side effects, but no unexpected safety issues have been reported.

Both treatments serve as important options for kidney transplant recipients and have undergone thorough study to ensure their safety. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about Envarsus XR for kidney transplant recipients because it offers a once-daily dosing option, compared to the traditional twice-daily tacrolimus. This can significantly improve convenience and adherence to medication schedules for patients. Additionally, Envarsus XR uses an extended-release formulation, which may provide more stable blood levels of the drug, potentially reducing side effects and improving overall outcomes. This new delivery method sets it apart from the immediate-release tacrolimus, which requires more frequent dosing.

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

This trial will compare the effectiveness of Envarsus XR, taken once daily, with immediate-release tacrolimus, taken twice daily, for kidney transplant recipients. Studies have shown that both Envarsus XR and immediate-release tacrolimus are effective for kidney transplant patients. Research indicates that Envarsus XR matches the effectiveness of the twice-daily immediate-release version in protecting both the patient and the transplanted kidney over one year. Immediate-release tacrolimus has long improved outcomes for kidney transplant patients. These findings suggest that both forms of tacrolimus are viable options for managing kidney transplants, with Envarsus XR offering the convenience of once-daily dosing. ^{1 2 4 5 6}

Who Is on the Research Team?

Mark Stegall, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

Adult kidney transplant recipients who can follow the study's procedures and have signed a consent form are eligible. Those on belatacept, azathioprine, mTOR inhibitors like sirolimus or everolimus, or with professional caretakers handling their meds cannot join.

Inclusion Criteria

Patient is able to comply with study procedures for the entire length of the study.

I have received a kidney transplant from a living or deceased donor.

Patient has been informed about the study survey and has signed an informed consent form.

Exclusion Criteria

Patient is in a setting where a professional care taker is responsible for dispensing subject's medication.

I am currently taking medication that includes sirolimus or everolimus.

I am currently taking azathioprine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either once-daily Envarsus XR® or twice-daily immediate release tacrolimus

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Envarsus XR
• Tacrolimus immediate release

Trial Overview

The trial is testing if once-daily Envarsus XR (extended-release tacrolimus) leads to fewer side effects and better quality of life compared to twice-daily immediate release tacrolimus in kidney transplant patients.

How Is the Trial Designed?

Group I: Envarsus XR Active Control 1 Intervention

Subjects assigned to this arm will take Envarsus XR one time daily by mouth, at the clinically prescribed dose.

Group II: Tacrolimus twice-daily Active Control 1 Intervention

Subjects assigned to this arm will take tacrolimus two times daily by mouth, at the clinically prescribed dose.

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Veloxis Pharmaceuticals

Industry Sponsor

Trials

43

Recruited

3,200+

Published Research Related to This Trial

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]

Extended-release tacrolimus (tacrolimus ER) is as effective as the traditional twice-daily formulation in preventing transplant rejection in adult kidney transplant recipients, based on phase III/IV trials with follow-up up to 4 years.

Tacrolimus ER shows better renal function compared to ciclosporin and has a similar tolerability profile to the original formulation, making it a convenient once-daily option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended-release tacrolimus: a review of its use in de novo kidney transplantation. McCormack, PL.[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]

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]

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

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envarsusxr.com

envarsusxr.com/hcp/efficacy-safety

Clinical Data | ENVARSUS XR® (tacrolimus extended- ...

Patient and graft protection at 1 and 2 years. *Treatment failure was a composite endpoint of biopsy-proven acute rejection, graft failure, death, and loss to ...

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 ...

1-year data from this trial showed the noninferiority of a novel once-daily extended-release tacrolimus (LCPT; Envarsus XR) to immediate-release tacrolimus (IR- ...

4.

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.

5.

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.

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, ...