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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines two types of tacrolimus, a drug that prevents kidney transplant complications, to assess their effects on blood vessel health and safety. One type is a once-daily extended-release tablet (Extended Release Tacrolimus Tablets), and the other is a twice-daily capsule (Immediate Release Tacrolimus Capsule). The trial focuses on pulse wave velocity and vascular compliance, which measure blood vessel function. Suitable participants have had a kidney transplant, identify as non-Hispanic Black, and are on specific medications to prevent organ rejection. As a Phase 4 trial, this research involves an FDA-approved treatment and aims to understand its benefits for more patients.

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 is the safety track record for these treatments?

Research has shown that both extended-release and immediate-release tacrolimus are generally well-tolerated by kidney transplant recipients. The extended-release version, Envarsus XR, can cause common side effects such as diarrhea, low red blood cell count (anemia), and urinary tract infections in about 15% of patients. However, it is overall considered safe for these patients.

Studies on the immediate-release version, Prograf, indicate it may cause similar side effects, including the possibility of developing diabetes after the transplant. Both versions can potentially affect kidney function, so monitoring for any changes in urination is important. Despite these possible side effects, both forms have been successfully used in many transplant patients. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for kidney transplant complications because they offer different dosing regimens that could improve patient convenience and adherence. The Extended Release Tacrolimus Tablets are taken once daily, which is a significant improvement over the Immediate Release Tacrolimus Capsules that need to be taken twice a day. This once-daily dosing could make it easier for patients to manage their medication routine, potentially enhancing compliance and reducing the risk of organ rejection due to missed doses. Both treatments are used in combination with rabbit antithymocyte globulin (rATG), oral mycophenolate mofetil (MMF), and oral steroids, but the convenience of the extended-release formulation is what sets it apart.

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

This trial will compare the effectiveness of extended-release and immediate-release tacrolimus in preventing organ rejection after kidney transplants. Participants in one arm will receive the extended-release version, Envarsus XR, taken once a day. Studies have indicated that Envarsus XR is safe and effective for kidney transplant patients. Participants in another arm will receive the immediate-release version, Prograf, taken twice a day. Research has shown that Prograf has a strong history of safety and effectiveness for these patients. Both treatment options are well-regarded, offering reliable choices for managing transplant health. ^{5 6 7 8 9}

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3979830/

Long-Term Follow-Up of a Phase III Clinical Trial ... Two-year data showed no unexpected safety or efficacy signals with Astagraf XL in renal transplant recipients (6). Since then, extended-release tacrolimus has ...

2. 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, ...

3. 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].

4. 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- ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2015/206406Orig1s000SumR.pdf

206406Orig1s000 - accessdata.fda.gov ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/204096s009lbl.pdf

ASTAGRAF XL (tacrolimus) Label - accessdata.fda.gov ASTAGRAF XL caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and ...

7. envarsusxr.com envarsusxr.com/hcp/efficacy-safety

Clinical Data | ENVARSUS XR® (tacrolimus extended- ... De Novo kidney transplant patients: Most common adverse reactions (incidence ≥15%) reported with ENVARSUS XR are diarrhea, anemia, urinary tract infection, ...

8. mayoclinic.org mayoclinic.org/drugs-supplements/tacrolimus-oral-route/description/drg-20068314

Tacrolimus (oral route) - Side effects & dosage This medicine may cause kidney problems. Check with your doctor right away if you have blood in your urine, change in frequency of urination or ...

9. astagrafxl.com astagrafxl.com/side-effects

What are the possible side effects of ASTAGRAF XL? The most common side effects of ASTAGRAF XL are diarrhea, constipation, nausea, swelling of the hands, ankles, or legs, and tremors (shaking of the body).