Tacrolimus Regimens for Kidney Transplant Complications

(PTAAK Trial)

Recruiting in Palo Alto (17 mi)

Overseen by Roy D Bloom, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Waitlist Available

Sponsor: Roy D. Bloom, MD

No Placebo Group

Prior Safety Data

Trial Summary

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.

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 4 5}

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 6}

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 4 5}

Eligibility Criteria

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

Treatment Details

Interventions

• Extended Release Tacrolimus Tablets (Immunosuppressant)
• Immediate Release Tacrolimus Capsule (Immunosuppressant)

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.

Participant Groups

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, United States, 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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Hospital of the University of Pennsylvania Philadelphia, PA

Who Is Running the Clinical Trial?

Roy D. Bloom, MD Lead Sponsor

Veloxis Pharmaceuticals Industry Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

Advagraf® with or without an induction therapy for de novo kidney-transplant recipients. [2021] Cornerstone immunosuppressive therapy currently relies on immediate-release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf®/Astagraf XL®, Astellas company) and a long-lasting formulation (Envarsus®, Veloxis company). Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf®/Astagraf XL®) used in conjunction with or without an induction therapy (i.e., basiliximab) in de novo kidney-transplant recipients. To achieve this, we searched for suitable articles through PubMed. Expert commentary: Phases-III and -IV studies comparing Advagraf®/Astagraf XL® to Prograf® in association with mycophenolate mofetil (more than 2,500 patients) have demonstrated overall similar results with regards to patient/graft survival, biopsy-proven acute-rejection rate, and renal function (p > 0.05). A randomized controlled study in maintenance kidney transplant patients has shown (using electronic monitoring) that, as compared to Prograf®, Advagraf® significantly improved adherence to medication. Other studies report that Advagraf®-treated patients receiving a mTOR-inhibitor agent (sirolimus or everolimus) instead of MMF: this was associated with good allograft outcome, and might also prevent late-onset cytomegalovirus infection. Advagraf®-based immunosuppression given to de novo kidney-transplant recipients, with or without an induction therapy, provided excellent results compared to Prograf®; it also increased patients' adherence to treatment.

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] In a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported.

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

Overview of extended release tacrolimus in solid organ transplantation. [2022] Tacrolimus (Prograf(©), Astellas Pharma Europe Ltd, Staines, United Kingdom; referred to as tacrolimus-BID) is an immunosuppressive agent to prevent and treat allograft rejection in kidney transplant recipients in combination with mycophenolate mofetil, corticosteroids, with or without basiliximab induction. The drug has also been studied in liver, heart and lung transplant; however, these are currently off-label indications. An extended release tacrolimus formulation (Advagraf(©), Astagraf XL(©)) allows for once-daily dosing, with the potential to improve adherence. Extended release tacrolimus has similar absorption, distribution, metabolism and excretion to tacrolimus-BID. Phase I pharmacokinetic trials comparing extended release tacrolimus and tacrolimus-BID have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration (tmax) with the extended release formulation; however, AUC0-24 was comparable between formulations. Overall extended release tacrolimus has a very similar safety and efficacy profile to tacrolimus-BID. It is not recommended in the use of liver transplant patient's due to the increased risk of mortality in female recipients. There has been minimal data regarding the use of extended release tacrolimus in heart and lung transplant recipients. With the current data available for all organ groups the extended release tacrolimus should be dosed in a 1:1 fashion, the exception may be the cystic fibrosis population where their initial dose may need to be higher.

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] After organ transplant, strategies to simplify the therapeutic regimen may improve adherence and prevent rejection and/or graft loss. The aim of the present study was to evaluate the safety of conversion from once-daily prolonged-release tacrolimus (Advagraf; Astellas Pharma Europe Limited, Middlesex, UK) to once-daily extended-release tacrolimus (Envarsus; Chiesi SAS, Nanterre, France) in stable adult liver transplant recipients.

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

Extended-release tacrolimus: a review of its use in de novo kidney transplantation. [2022] Extended-release tacrolimus (tacrolimus ER) [Advagraf(®); Astagraf XL(®); Graceptor(®); Prograf XL(®)] is a once-daily formulation of the immunosuppressive calcineurin inhibitor, which is approved in many countries worldwide for the prophylaxis of transplant rejection in adult de novo kidney transplant recipients. It is absorbed more slowly than the conventional, twice-daily, immediate-release formulation, initially producing lower exposure when administered at the same daily dosage, but providing equivalent exposure upon repeat administration with therapeutic drug monitoring. In randomized, controlled, phase III/IV trials, with extended follow-up to 4 years, the efficacy of tacrolimus ER was similar to that of twice-daily tacrolimus with regard to the prevention of acute rejection or graft dysfunction in adult de novo kidney transplant recipients. Renal function was significantly better with tacrolimus ER, but not tacrolimus, than with ciclosporin. The tolerability profile of tacrolimus ER was descriptively similar to that of the original twice-daily formulation, with no notable differences. Therefore, tacrolimus ER retains the immunosuppressive activity of the original formulation in the prophylaxis of transplant rejection in adult de novo kidney transplant recipients and offers the benefits of once-daily administration.

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

Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients. [2022] Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf(®), a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf(®) and Envarsus(®) XR) and various generic versions of Prograf(®) are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf(®), Advagraf(®) and Envarsus(®) XR are not bioequivalent [in terms of the area under the concentration-time curve from 0 to 24 h (AUC0-24) or the minimum concentration (C min)]. Patients may require a daily dosage increase if converted from Prograf(®) to Advagraf(®), while a daily dosage reduction appears necessary for conversion from Prograf(®) to Envarsus(®) XR. Prograf(®) itself, or generic immediate-release tacrolimus, can be administered in a once-daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC0-24 and C min is variable and not strong for all three formulations, indicating that trough measurements may not always give a good indication of overall drug exposure. Further investigation is required into whether the prolonged-release formulations have reduced within-subject pharmacokinetic variability, which would be a distinct advantage. Whether the effects of factors that influence tacrolimus absorption and pre-systemic metabolism (patient genotype status; gastrointestinal disease and disorders) and drug interactions differ across the formulations needs to be further elucidated. Most pharmacokinetic comparison studies to date have involved relatively stable patients, and many have been sponsored by the pharmaceutical companies manufacturing the new formulations. Larger randomized, controlled trials are needed in different transplant populations to determine whether there are differences in efficacy and toxicity across the formulations and whether formulation conversion is worthwhile in the longer term. While it has been suggested that once-daily administration of tacrolimus may improve patient compliance, further studies are required to demonstrate this. Mistakenly interchanging different tacrolimus formulations can lead to serious patient harm. Once-daily tacrolimus is now available as an alternative to twice-daily tacrolimus and can be used de novo in solid-organ transplant recipients or as a different formulation for existing patients, with appropriate dosage modifications. Clinicians need to be fully aware of pharmacokinetic and possible outcome differences across the different formulations of tacrolimus.