Simplified Immunosuppression for Kidney Transplant

(SIMPLE Trial)

Overseen By Melissa Ramos, BSN

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Southern California

Disqualifiers: Repeat transplants, cPRA >20%, skin cancer, 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

80 Participants Needed

Trial Summary

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, since the study involves specific immunosuppressive drugs, you may need to adjust your current medication regimen. Please consult with the study team for guidance.

What data supports the idea that Simplified Immunosuppression for Kidney Transplant is an effective treatment?

The available research shows that mycophenolate mofetil (MMF), a drug used in Simplified Immunosuppression for Kidney Transplant, is associated with a lower rate of acute rejection compared to azathioprine (AZA). Specifically, MMF results in a 50% lower incidence of acute rejection. Additionally, some studies suggest better long-term kidney survival with MMF compared to AZA, although results vary across different studies. This indicates that MMF may be more effective in preventing the body from rejecting the transplanted kidney. ^{1 2 3 4 5}

What safety data is available for immunosuppressive treatments in kidney transplants?

The safety of mycophenolate mofetil (MMF) compared to azathioprine (Aza) in kidney transplantation has been evaluated in several studies. A systematic review focused on their side effects, and another study investigated the safety of converting from MMF to Aza in stable renal transplant patients. These studies provide evidence-based insights into the safety profiles of these immunosuppressive treatments. ^{2 3 4 5 6}

Is the drug combination of Azathioprine, Methylprednisolone, prednisone, Mycophenolate mofetil (MMF) or Mycophenolic acid (MPA), Once-daily envarsus XR, and Tacrolimus a promising treatment for kidney transplant?

Yes, the drug combination is promising for kidney transplant. Studies show that using Mycophenolate mofetil (MMF) with Tacrolimus leads to better outcomes, like fewer cases of the body rejecting the new kidney, compared to using Azathioprine. This combination is effective and safe for kidney transplant patients. ^{2 3 4 5 7}

What is the purpose of this trial?

The purpose of this study is to determine if the combination of once-daily tacrolimus extended-release (EnvarsusXR) and Azathioprine is non inferior with respect to the composite outcome of acute rejection, graft and patient survival as compared to a combination of twice-daily immediate release tacrolimus and mycophenolate mofetil/mycophenolic acid.

Research Team

Santhi Voora, MD

Principal Investigator

University of Southern California

Eligibility Criteria

This trial is for adults aged 18-85 who have recently received a kidney transplant. They should have a cold ischemia time of less than 24 hours if there's a significant mismatch in donor and recipient tissue types, or more than 24 hours for fewer mismatches. Their pre-transplant antibody levels must be low (≤20%).

Inclusion Criteria

Your cPRA test results must be less than 20% before getting a transplant.

My organ transplant matches well if cold time is under 24 hours for 3-6 mismatches, and over 24 hours for less than 3 mismatches.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either a once-daily regimen of EnvarsusXR and azathioprine or a twice-daily regimen of immediate release tacrolimus and mycophenolate mofetil/mycophenolic acid

12 months

Monthly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of graft function and side effects

3 months

Treatment Details

Interventions

• Azathioprine
• Methylprednisolone, prednisone
• Mycophenolate mofetil (MMF) or Mycophenolic acid (MPA)
• Once-daily envarsus XR
• Tacrolimus

Trial Overview The study tests whether taking EnvarsusXR (a once-daily tacrolimus) with Azathioprine works as well as the standard treatment of twice-daily Tacrolimus with Mycophenolate mofetil/acid to prevent organ rejection without affecting patient survival.

Participant Groups

Group I: Twice-daily Regimen Active Control 4 Interventions

Twice-daily regimen of immediate release tacrolimus, mycophenolate mofetil (MMF)/mycophenolic acid (MPA) plus daily methylprednisolone or prednisone.

Group II: Once-daily Regimen Active Control 4 Interventions

Once-daily regimen of Envarsus, azathioprine plus methylprednisolone or prednisone.

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?

University of Southern California

Lead Sponsor

Trials

956

Recruited

1,609,000+

Veloxis Pharmaceuticals

Industry Sponsor

Trials

43

Recruited

3,200+

Findings from Research

In a retrospective study comparing mycophenolate mofetil (MMF) and azathioprine (AZA) in renal transplantation, no significant difference in long-term graft survival was found between the two immunosuppressive regimens, despite MMF showing a lower incidence of acute rejection shortly after transplantation.

The study suggests that early benefits of MMF in reducing acute rejection may not lead to improved long-term outcomes, potentially due to various non-immunological factors affecting graft survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of long-term actual renal allograft survival in mycophenolate mofetil and azathioprine-based triple drug immunosuppression protocols. Attallah, N., Goggins, M., Nori, U., et al.[2016]

Mycophenolate acid (MMF) at a dosage of 2 g/day is more effective than azathioprine (AZA) in improving graft and long-term patient survival rates after renal transplantation, based on a review of 23 randomized controlled trials.

Both MMF dosages (2 g/day and 3 g/day) significantly reduce the incidence of biopsy-proven rejection compared to AZA, with the 2 g/day dosage being more acceptable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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

In a study of 87 stable renal transplant patients, switching from mycophenolate mofetil (MMF) to Azathioprine (AzA) after 6 months did not negatively impact graft survival or increase acute rejection rates over a 12-month follow-up.

While the conversion to AzA was deemed safe and necessary in certain economic contexts, it was associated with a higher incidence of reversible side effects like liver lesions and leukocytopenia compared to those who continued on MMF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Necessity and safety of conversion from mycophenolate mofetil to AzA thioprine after renal transplantation]. Lu, JS., Xiao, XR., Ao, JH., et al.[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]

In a study of 20 kidney transplant patients, the generic form of mycophenolate mofetil (Immucept®) showed a comparable pharmacokinetic profile to the original formulation (CellCept®), with no significant differences in drug concentration levels.

Most patients maintained an adequate level of mycophenolic acid (MPA AUC0-12 > 30.0 μg⋅hr/mL) while on both medications, suggesting that the generic version is a viable alternative for immunosuppression post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Study of the Pharmacokinetic Comparison between the Generic and Original Form of Mycophenolate Mofetil Among Thai Renal Transplant Patients. Larpparisuth, N., Pinpaiboon, S., Ratchawang, N., et al.[2019]

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 study of 223 kidney transplant recipients followed for 2 years, the combination of tacrolimus and mycophenolate mofetil (MMF) showed the best kidney function and overall outcomes compared to other regimens.

Patients treated with tacrolimus+MMF had a 23% increase in allograft survival in cases of delayed graft function compared to those on cyclosporine+MMF, highlighting the potential benefits of this combination for specific patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years. Ahsan, N., Johnson, C., Gonwa, T., et al.[2022]

References

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

Comparison of long-term actual renal allograft survival in mycophenolate mofetil and azathioprine-based triple drug immunosuppression protocols. [2016]

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

Efficacy of mycophenolate mofetil versus azathioprine after renal transplantation: a systematic review. [2018]

3. China pubmed.ncbi.nlm.nih.gov

[Necessity and safety of conversion from mycophenolate mofetil to AzA thioprine after renal transplantation]. [2016]

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

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

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

A Study of the Pharmacokinetic Comparison between the Generic and Original Form of Mycophenolate Mofetil Among Thai Renal Transplant Patients. [2019]

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

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

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

Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years. [2022]