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

(SIMPLE Trial)

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

240 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The purpose of this study is to compare once-daily tacrolimus extended-release (Envarsus XR®) to twice-daily immediate release tacrolimus to find out if people taking tacrolimus extended release (Envarsus XR®) report fewer side effects, increased medication compliance and higher scores on quality of life assessments compared to people taking twice daily tacrolimus immediate release.

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.

Is once-daily tacrolimus safe for kidney transplant recipients?

Once-daily tacrolimus formulations like Envarsus XR and Advagraf have been shown to be generally safe for kidney transplant recipients, with similar safety profiles to the traditional twice-daily tacrolimus. Studies indicate that these formulations are effective and safe when used with other medications like mycophenolate mofetil and corticosteroids. ^{1 2 3 4 5}

How is the drug Envarsus XR different from other tacrolimus formulations for kidney transplant recipients?

Envarsus XR is a once-daily extended-release formulation of tacrolimus that uses MeltDose™ technology to improve drug bioavailability, resulting in more consistent drug levels in the body and potentially better adherence compared to the traditional twice-daily immediate-release tacrolimus. ^{1 2 6 7 8}

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

Research shows that the once-daily extended-release tacrolimus (Envarsus XR) is as effective as the twice-daily immediate-release version for kidney transplant patients, with similar safety and efficacy outcomes. ^{1 2 4 5 7}

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 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]

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]

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 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]

Citations

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

Novel Once-Daily Extended-Release Tacrolimus Versus Twice-Daily Tacrolimus in De Novo Kidney Transplant Recipients: Two-Year Results of Phase 3, Double-Blind, Randomized Trial. [2016]

2. 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]

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]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. [2023]

6. England pubmed.ncbi.nlm.nih.gov

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

7. Switzerland pubmed.ncbi.nlm.nih.gov

Conversion to prolonged release tacrolimus formulation in stable kidney transplant recipients. [2018]

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

Extended-release tacrolimus: a review of its use in de novo kidney transplantation. [2022]