Once vs Twice Daily Immunosuppression for Kidney Complications

No longer recruiting at 1 trial location

Overseen By Tarek Alhamad, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Washington University School of Medicine

Disqualifiers: Non-renal transplant, 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: 3

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the best way to manage kidney transplant issues by comparing two medication schedules. One group will follow a once-daily regimen (Envarsus and azathioprine), while the other will adhere to a twice-daily plan (tacrolimus and mycophenolic acid). The trial seeks to determine which schedule is easier to follow, causes fewer side effects, and results in fewer biopsy-confirmed rejection episodes. Individuals who have undergone a kidney transplant and received thymoglobulin during surgery may be suitable candidates for this trial. 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 to join the trial?

The trial protocol does not specify whether you need to stop your current medications. However, since the study involves specific immunosuppressive regimens, you may need to adjust your current medications. Please consult with the trial coordinators for more details.

What is the safety track record for these treatments?

Research has shown that both treatment options in this study have been used previously in kidney transplant patients, with safety data available.

For the once-daily treatment with Envarsus (a long-acting form of tacrolimus) and azathioprine, studies have found common side effects such as diarrhea, low red blood cell count (anemia), and urinary tract infections. The FDA has already approved Envarsus to prevent organ rejection in kidney transplant patients, indicating a known safety record. Some studies suggest it might cause fewer side effects compared to other forms of tacrolimus.

For the twice-daily treatment with tacrolimus and mycophenolic acid, research indicates these drugs are crucial for preventing organ rejection. Common side effects include digestive issues and low blood cell counts. Reviews of tacrolimus-based treatments have found them generally safe for kidney transplant patients.

Overall, both treatment options have been used successfully and have known side effects, which are monitored to ensure patient safety. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about the trial comparing once and twice daily immunosuppression for kidney complications because it explores how different dosing regimens might improve patient outcomes. Unlike the standard of care, which typically involves a twice-daily regimen, the once-daily option using Envarsus and azathioprine may offer increased convenience and better adherence, potentially enhancing the quality of life for patients. The twice-daily regimen with Tacrolimus and mycophenolic acid remains a strong competitor, as it is the current standard, but understanding if less frequent dosing can maintain or improve effectiveness is a significant focus. Researchers hope to discover whether the simplified once-daily dosing can still achieve the necessary immunosuppressive effects without sacrificing efficacy.

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

In this trial, participants will be assigned to one of two treatment regimens. Research has shown that taking Envarsus and azathioprine once a day is effective for kidney transplant patients. This once-daily regimen matches other options in preventing organ rejection and has a similar safety profile. Envarsus, a long-acting form of tacrolimus, simplifies dosing and may improve adherence to the treatment plan.

For the twice-daily regimen, participants will receive tacrolimus and mycophenolic acid. These medications are crucial in preventing organ rejection after kidney transplants. Tacrolimus has a proven history of improving transplant success and is a key component of many treatment plans. Mycophenolic acid works with tacrolimus to enhance effectiveness and reduce the risk of rejection. Both treatment options in this trial have demonstrated strong results in maintaining kidney health after a transplant. ^{1 2 5 6 7}

Who Is on the Research Team?

Rowena Delos Santos

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

This trial is for adults over 18 who have received a kidney transplant and were treated with Thymoglobulin. It's not suitable for those who've had non-kidney organ transplants, can't take Envarsus post-transplant, or were discharged to an acute care facility after their transplant.

Inclusion Criteria

I have received Thymoglobulin induction therapy.

I have received a kidney transplant.

Exclusion Criteria

I was moved to a specialized care facility after my transplant.

I cannot take Envarsus after my transplant.

I have had an organ transplant that is not a kidney.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a once daily or twice daily immunosuppressive medication regimen

12 months

Regular visits as per protocol

Follow-up

Participants are monitored for compliance, tolerability, and biopsy proven rejection

12 months

Follow-up assessments at 3 and 12 months post transplant

What Are the Treatments Tested in This Trial?

Interventions

• Azathioprine
• Envarsus
• Mycophenolic Acid
• Tacrolimus

Trial Overview The study compares two immunosuppression regimens in kidney transplant recipients: one group will take Envarsus/azathioprine once daily, while the other will take tacrolimus/mycophenolic acid twice daily. The goal is to see which regimen leads to better compliance and fewer rejections.

How Is the Trial Designed?

Group I: Once daily regimen Active Control 1 Intervention

Once daily medication regimen (Envarsus and azathioprine)

Group II: Twice daily regimen Active Control 1 Intervention

Twice daily medication regimen (Tacrolimus and mycophenolic acid)

Azathioprine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Imuran for:

• Prevention of rejection in organ transplantation
• Treatment of autoimmune diseases such as rheumatoid arthritis

Approved in United States as Imuran for:

• Prevention of rejection in organ transplantation
• Treatment of rheumatoid arthritis

Approved in Canada as Imuran for:

• Prevention of rejection in organ transplantation
• Treatment of rheumatoid arthritis

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Veloxis Pharmaceuticals

Industry Sponsor

Trials

43

Recruited

3,200+

Published Research Related to This Trial

Mycophenolate mofetil (MMF) is associated with a higher incidence of gastrointestinal side effects, such as diarrhea, and increased risk of CMV infections compared to azathioprine (Aza) in renal transplantation, based on a review of 20 trials involving 6387 patients.

While MMF (3 g/d) showed higher rates of leukopenia compared to Aza, the lower dose of MMF (2 g/d) did not significantly differ from Aza, indicating that dosage may influence the safety profile of MMF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of mycophenolate mofetil versus azathioprine in renal transplantation: a systematic review. Wang, K., Zhang, H., Li, Y., et al.[2018]

In a long-term study of 133 kidney transplant patients followed for an average of 13.8 years, there were no significant differences in patient or graft survival, cancer incidence, or kidney function between those treated with mycophenolate mofetil (MMF) and those treated with azathioprine (AZA).

While the group receiving 3 g/d of MMF showed the best death-censored graft survival, the overall findings suggest that MMF does not demonstrate clear long-term advantages over AZA, with a notable 42% of the MMF group switching to AZA by 5 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mycophenolate versus azathioprine for kidney transplantation: a 15-year follow-up of a randomized trial. Clayton, PA., McDonald, SP., Chapman, JR., et al.[2016]

Mycophenolate mofetil (MMF) significantly reduces the incidence of acute renal allograft rejection, with rates dropping from 46.4% in the placebo group to 17.0% and 13.8% in the MMF groups (2 g and 3 g doses, respectively) after six months in a study of 491 patients.

MMF has a favorable safety profile, showing no significant drug interactions and primarily causing gastrointestinal issues, similar to the adverse effects seen with traditional therapies like azathioprine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of clinical experience with the novel immunosuppressive drug mycophenolate mofetil in renal transplantation. Behrend, M.[2016]

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]

Enteric-coated mycophenolate sodium (EC-MPS) is shown to be therapeutically equivalent to mycophenolate mofetil (MMF) in renal transplant patients, based on a large-scale study involving 122 patients during the 12- to 36-month posttransplant period.

The safety profiles of EC-MPS and MMF were similar, with comparable rates of adverse events, infections, and graft loss, confirming that EC-MPS is a safe and effective alternative for maintenance therapy in kidney transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term administration of enteric-coated mycophenolate sodium in kidney transplant patients. Salvadori, M.[2016]

The combination of tacrolimus and mycophenolate mofetil has been widely studied since the mid-1990s for immunosuppression in kidney transplants, but clinical trial outcomes have varied due to differences in treatment protocols and study designs.

This review aims to critically analyze existing literature to provide a comprehensive overview of the efficacy and safety of tacrolimus and mycophenolate mofetil combination therapy in renal transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients. Dalal, P., Shah, G., Chhabra, D., et al.[2021]

In a study of 667 kidney transplant recipients, the once-daily tacrolimus (Tacrolimus QD) showed a comparable efficacy to the twice-daily formulation (Tacrolimus BID) in preventing acute rejection, with rates of 20.4% and 15.8% respectively, although the QD formulation was just outside the noninferiority margin.

Both formulations demonstrated similar patient and graft survival rates at 12 months (97.5% and 96.9% for patient survival, and 92.8% and 91.5% for graft survival), indicating that Tacrolimus QD is a safe and effective alternative to the established BID regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Krämer, BK., Charpentier, B., Bäckman, L., et al.[2023]

In a 24-month study of 101 kidney transplant recipients, the enteric-coated formulation of mycophenolate sodium (EC-MPS) showed a significantly lower incidence of serious infections compared to mycophenolate mofetil (MMF), with rates of 40% for EC-MPS and 49% for MMF.

The therapeutic effects of EC-MPS were found to be similar to those of MMF, as indicated by comparable serum creatinine levels and rates of biopsy-proven acute rejection, suggesting that EC-MPS is a safe and effective alternative in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enteric-coated mycophenolate sodium given in combination with tacrolimus has a lower incidence of serious infections in Asian renal-transplant recipients compared with mycophenolate mofetil. Feng, JJ., Zhang, LW., Zhao, P., et al.[2016]

Switching from azathioprine (AZA) to mycophenolate mofetil (MMF) in a triple therapy regimen for kidney transplant patients significantly reduced the rate of acute rejection episodes from 60% to 20% over 6 months, indicating improved efficacy of MMF.

Although the cost of immunosuppressive therapy increased by 1.5 times with MMF, the overall costs associated with treating rejection episodes decreased significantly, leading to fewer diagnostic procedures and hospitalizations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil. Wüthrich, RP., Weinreich, T., Ambühl, PM., et al.[2019]

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]

In a long-term study of 150 kidney transplant recipients, both mycophenolate mofetil and enteric-coated mycophenolate sodium showed similarly low rates of biopsy-proven acute rejection (BPAR) and high renal function at 48 months post-transplant, indicating both medications are effective.

The study found no significant differences in patient/graft survival rates or the incidence of adverse events, such as gastrointestinal side effects and infections, suggesting that both treatments have comparable safety profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of mycophenolate mofetil versus enteric-coated mycophenolate sodium in primary renal transplantation with tacrolimus and steroid avoidance: four-year analysis. Ciancio, G., Gaynor, JJ., Zarak, A., et al.[2022]

In a 9-month study involving 123 kidney transplant recipients, switching from once-daily Advagraf to a generic tacrolimus preparation was found to be safe, with no cases of acute rejection or graft loss reported.

The conversion required a 17% reduction in the tacrolimus dose to maintain stable renal function, as indicated by consistent serum creatinine levels throughout the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of conversion from Advagraf to twice-daily generic tacrolimus in kidney transplant recipients: a single-center study. Melo, MJ., Gonçalves, J., Guerra, JO., et al.[2018]

In a study involving 248 renal transplant recipients, mycophenolate mofetil (MMF) did not show superior efficacy compared to azathioprine in preventing acute rejection or improving long-term kidney function, with a mean difference in estimated GFR of only 4.67 ml/min after 5 years.

Both MMF and azathioprine had similar long-term outcomes regarding patient mortality, graft loss, and adverse events, suggesting that azathioprine may be a more cost-effective option for immunosuppression in kidney transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mycophenolate mofetil versus azathioprine for prevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinical trial. Remuzzi, G., Cravedi, P., Costantini, M., et al.[2016]

Citations

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Clinical Data | ENVARSUS XR® (tacrolimus extended- ... New Onset Diabetes after Transplant: ENVARSUS XR caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03979365

Envarsus XR Compared to Immediate Release Tacrolimus The investigators hypothesize that the use of once-daily Envarsus XR® could decrease some transplant- and tacrolimus-related adverse symptoms and potentially ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10946132/

Management of kidney transplant recipients for primary ... This review aims to provide primary care practitioners with a practical blueprint for outpatient care of kidney transplant recipients.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04773392

Simplified IMmunosuppressive Protocol Utilizing Low Dose ... The investigators seek to demonstrate that a once-daily regimen, including EnvarsusXR and azathioprine, will be at least equally effective with respect to acute ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0272638615013451

Novel Once-Daily Extended-Release Tacrolimus Versus ... Results suggest that once-daily LCPT in de novo kidney transplantation has comparable efficacy and safety profile to that of IR-Tac.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2018/206406s007lbl.pdf

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

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9010272/

A randomized crossover study comparing different ... A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long‐term outcomes after kidney transplantation.