Once vs Twice Daily Immunosuppression for Kidney Complications

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: Unknown

51 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to determine whether an immunosuppressive maintenance regimen of Envarsus/azathioprine compared to a tacrolimus/ mycophenolic acid regimen is associated with better compliance, tolerability, and lower biopsy proven rejection.

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 data supports the idea that Once vs Twice Daily Immunosuppression for Kidney Complications is an effective drug?

The available research shows that using drugs like tacrolimus and mycophenolate mofetil together can help prevent organ rejection in kidney transplant patients. One study found that mycophenolate mofetil, when used with other drugs, reduces the rate of kidney transplant rejection in the first 6 months. Another study compared mycophenolate mofetil with azathioprine and found that both drugs had similar long-term outcomes, but mycophenolate mofetil was more expensive. Additionally, a trial showed that using enteric-coated mycophenolate sodium with tacrolimus resulted in fewer serious infections compared to mycophenolate mofetil. Overall, these studies suggest that these drugs are effective in managing kidney complications after transplantation. ^{1 2 3 4 5}

What safety data is available for once vs twice daily immunosuppression in kidney transplants?

The safety data for once-daily (Advagraf) versus twice-daily (Prograf) tacrolimus in kidney transplants shows that both formulations have similar adverse event profiles and maintain renal function well over 12 months. A study found no significant difference in acute rejection rates between the two, supporting the use of once-daily tacrolimus as an effective alternative. Additionally, conversion from Prograf to Advagraf or generic tacrolimus has been shown to be safe. Envarsus, another once-daily formulation, has improved bioavailability and less variability in drug absorption, but no phase IV studies have shown its superiority over Advagraf in liver transplants. Safety comparisons between mycophenolate mofetil and azathioprine in renal transplantation have also been conducted, focusing on side effects. ^{6 7 8 9 10}

Is the drug combination of Azathioprine, Envarsus, Mycophenolic Acid, and Tacrolimus promising for kidney complications?

Yes, the combination of these drugs is promising for kidney complications. Tacrolimus and mycophenolate mofetil have been shown to effectively prevent organ rejection in kidney transplant patients. Mycophenolate mofetil is associated with less acute rejection compared to azathioprine. Enteric-coated mycophenolate sodium, similar to mycophenolate mofetil, is effective and safe for long-term use. Overall, these drugs together offer a strong approach to managing kidney complications. ^{2 3 11 12 13}

Research Team

Rowena Delos Santos

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

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 am 18 years old or older.

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.

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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 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]

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 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]

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]

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]

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]

References

1. United States 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. [2016]

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

Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients. [2021]

3. England 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. [2016]

4. United States 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. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil. [2019]

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

Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. [2023]

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

Impact of conversion from Advagraf to twice-daily generic tacrolimus in kidney transplant recipients: a single-center study. [2018]

8. 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]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Safety of mycophenolate mofetil versus azathioprine in renal transplantation: a systematic review. [2018]

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

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

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

Mycophenolate versus azathioprine for kidney transplantation: a 15-year follow-up of a randomized trial. [2016]

13. Germany pubmed.ncbi.nlm.nih.gov

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