Tacrolimus Regimens for Kidney Transplant Complications

(PTAAK Trial)

Overseen By Jennifer Trofe-Clark, Pharm D

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Roy D. Bloom, MD

Must be taking: Mycophenolate, Prednisone, Thymoglobulin

Disqualifiers: HIV, Severe liver disease, 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: 12 months

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

The primary purpose of this study is to evaluate the pulse wave velocity and vascular compliance measurements at the beginning and the end of the study while the participants are taking either extended release tacrolimus tablets (known by brand name Envarsus XR®, and also referred to as LCPT in this study) given once-daily each morning after transplantation or immediate release tacrolimus capsules (also known by brand name Prograf® or abbreviation IR-TAC in this study) that are administered twice-daily 12 hours apart after kidney transplantation. Pulse wave velocity and vascular compliance measurements are two non-invasive tests that are used to evaluate how well the blood vessels adapt to each heartbeat. The secondary purpose is to look at the effectiveness and safety of LCPT given once-daily compared to IR-TAC given twice-daily 12 hours apart after kidney transplantation.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop your current medications. However, it mentions that participants will be on specific immunosuppressants like Mycophenolate mofetil or mycophenolic sodium, and a prednisone taper or withdrawal protocol. It's best to discuss your current medications with the trial team.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants will be on specific immunosuppressive medications like Mycophenolate mofetil or mycophenolic sodium, along with Tacrolimus. It's best to discuss your current medications with the trial team.

What safety data exists for tacrolimus regimens in kidney transplant patients?

Safety data for tacrolimus regimens, including extended-release formulations like Advagraf/Astagraf XL and Envarsus XR, show similar safety and efficacy profiles to immediate-release tacrolimus (Prograf). Studies indicate comparable patient and graft survival rates, acute rejection rates, and renal function. Extended-release formulations may improve medication adherence. However, they are not bioequivalent to immediate-release versions, requiring careful dosage adjustments and monitoring. Further research is needed to confirm long-term safety and efficacy across different formulations and patient populations. ^{1 2 3 4 5}

Is tacrolimus safe for kidney transplant patients?

Tacrolimus, including its extended-release forms like Advagraf and Astagraf XL, has been shown to have a similar safety profile to the immediate-release version (Prograf) in kidney transplant patients. Studies indicate it is generally safe when used as part of an immunosuppressive regimen, although it requires careful monitoring due to its narrow therapeutic index (small margin between effective and harmful doses). ^{1 2 3 4 5}

Is the drug Extended Release Tacrolimus Tablets a promising treatment for kidney transplant complications?

Yes, Extended Release Tacrolimus Tablets are promising for kidney transplant complications. They offer the benefit of once-daily dosing, which can improve patient adherence to medication. Studies show that this drug is effective in preventing organ rejection and maintaining kidney function, similar to the traditional twice-daily version. It also has a comparable safety profile, making it a reliable option for kidney transplant patients. ^{1 2 3 5 6}

How is the drug Tacrolimus Regimens for Kidney Transplant Complications different from other treatments?

The extended-release tacrolimus formulations (like Advagraf®/Astagraf XL®) offer the benefit of once-daily dosing, which can improve patient adherence compared to the traditional twice-daily immediate-release tacrolimus. This formulation provides similar efficacy in preventing transplant rejection while potentially offering better renal function and a similar safety profile. ^{1 2 3 5 6}

What data supports the idea that Tacrolimus Regimens for Kidney Transplant Complications is an effective drug?

The available research shows that extended-release tacrolimus, like Advagraf or Astagraf XL, is effective for kidney transplant patients. Studies have shown that it provides similar results to the immediate-release version, Prograf, in terms of patient survival and kidney function. Additionally, extended-release tacrolimus improves how well patients stick to their medication schedule, which is important for preventing organ rejection. Compared to another drug, cyclosporine, extended-release tacrolimus has better kidney function outcomes. Overall, it offers the same benefits as the original formulation but with the convenience of once-daily dosing. ^{1 2 3 5 6}

What data supports the effectiveness of the drug Tacrolimus Regimens for Kidney Transplant Complications?

Research shows that extended-release tacrolimus, like Advagraf or Astagraf XL, is as effective as the immediate-release version in preventing kidney transplant rejection. It also improves patient adherence to medication, which is crucial for successful transplant outcomes. ^{1 2 3 5 6}

Who Is on the Research Team?

Roy D Bloom, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for African American individuals with a BMI ≥19, undergoing their first or second kidney transplant. They must be using certain immunosuppressants and can have Hepatitis B or C. Excluded are those with severe GI issues affecting drug absorption, HIV positive, poor medical adherence history, women not using contraception unless exempted by specific criteria, anyone over 75 years old, recipients of more than two kidney transplants, and those allergic to Tacrolimus.

Inclusion Criteria

Subjects whose body mass index (BMI) ≥19

Subjects who are sero-positive for Hepatitis B or C positive may also be enrolled

Subjects who self-report their race/ethnicity as Black-non-Hispanic only (which may include self-reported African ancestry as African-American, Afro-Caribbean or African)

Exclusion Criteria

You are allergic to Tacrolimus or hydrogenated castor oil.

Subjects who are HIV positive at the time of pre-transplant screening

Subjects with WBC ≤ 2000/mm3 or ANC ≤ 1500 mm3 with PLT ≤ 75,000/mm3 or HGB < 8 g/dL

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either immediate release tacrolimus capsules or extended release tacrolimus tablets starting from the first day after kidney transplant

12 months

Monthly clinic visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including pulse wave velocity and vascular compliance measurements

12-24 months

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Extended Release Tacrolimus Tablets
• Immediate Release Tacrolimus Capsule

Trial Overview The study compares the effects on blood vessel function between two forms of the drug Tacrolimus: extended-release tablets taken once daily (Envarsus XR®) versus immediate-release capsules taken twice daily (Prograf®). It measures how well blood vessels respond to heartbeats before and after treatment in kidney transplant patients.

How Is the Trial Designed?

Group I: Extended Release Tacrolimus Tablets Active Control 1 Intervention

Dosed once daily in the morning and started at a dose of 0.14 mg/kg/day by the first day after kidney transplant (post-operative day 1). This medication will be given with rabbit antithymocyte globulin (rATG) induction, oral mycophenolate mofetil (MMF) and oral steroids to help prevent rejection. These medications will be ordered per standard of care both inpatient and outpatient.

Group II: Immediate Release Tacrolimus Capsules Active Control 1 Intervention

Dosed twice daily 12 hours apart and started at a dose of 0.1mg/kg/day by the first day after kidney transplant (post-operative day 1). This medication will be given with rabbit antithymocyte globulin (rATG) induction, oral mycophenolate mofetil (MMF) and oral steroids to help prevent rejection. These medications will be ordered per standard of care both inpatient and outpatient.

Extended Release Tacrolimus Tablets 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 converted from tacrolimus immediate-release formulations in combination with other immunosuppressants
• Prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants

Approved in United States as Prograf for:

• Prophylaxis of organ rejection in liver, kidney, and heart transplant recipients

Approved in United States as Astagraf XL for:

• Prophylaxis of organ rejection in kidney transplant recipients

Who Is Running the Clinical Trial?

Roy D. Bloom, MD

Lead Sponsor

Trials

1

Recruited

60+

Veloxis Pharmaceuticals

Industry Sponsor

Trials

43

Recruited

3,200+

Published Research Related to This Trial

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]

Extended release tacrolimus (Advagraf©, Astagraf XL©) offers a once-daily dosing option for kidney transplant recipients, potentially improving medication adherence while maintaining a similar safety and efficacy profile to the traditional twice-daily tacrolimus (Prograf©).

While extended release tacrolimus shows comparable pharmacokinetics to the standard formulation, it is not recommended for liver transplant patients due to an increased risk of mortality in female recipients, and there is limited data on its use in heart and lung transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overview of extended release tacrolimus in solid organ transplantation. Patel, N., Cook, A., Greenhalgh, E., et al.[2022]

Converting stable liver transplant patients from once-daily prolonged-release tacrolimus to once-daily extended-release tacrolimus is safe, with only two patients experiencing adverse effects that resolved after returning to the original medication.

This conversion not only reduced the mean daily cost of tacrolimus therapy from 5.54 to 4.11 Euros per patient but also required careful monitoring and dose adjustments to maintain effective serum levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients. Altieri, M., Delaval, G., Kimmoun, E., 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]

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. 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

Overview of extended release tacrolimus in solid organ transplantation. [2022]

4. Turkey pubmed.ncbi.nlm.nih.gov

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients. [2018]

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

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

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

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