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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a simpler, once-daily medication plan is as effective as the current twice-daily schedule for recent kidney transplant recipients. It compares two treatment combinations to determine if the new plan prevents kidney rejection as effectively as the old plan. Participants should be new kidney transplant recipients who have not had a previous transplant and do not possess certain antibodies that increase rejection risk. As a Phase 4 trial, the treatment is already FDA-approved and proven effective, and this research aims to understand how it benefits more patients.

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 is the safety track record for these treatments?

Research has shown that both treatment plans in the trial are safe based on previous studies. The once-daily Envarsus XR plan, which includes azathioprine, has proven safe in several clinical trials. The FDA has already approved this treatment for kidney transplant patients, indicating it is generally well-tolerated. However, some patients, such as African-American and Hispanic kidney transplant recipients, may face a higher risk for new health issues.

The twice-daily tacrolimus plan, combined with mycophenolate mofetil (MMF) or mycophenolic acid (MPA), is also safe and effective. Studies have demonstrated that it greatly improves outcomes for kidney transplant patients. Long-term follow-up data supports its safety, showing good patient and kidney survival rates.

Both treatment options have been thoroughly studied, and existing evidence confirms their safety for kidney transplant patients. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for kidney transplants because they aim to simplify immunosuppression regimens, potentially improving patient adherence and outcomes. Unlike the standard twice-daily regimen that includes immediate-release tacrolimus and mycophenolate mofetil, the once-daily regimen uses Envarsus XR, a formulation of tacrolimus that allows for more convenient dosing. This could lead to better adherence and potentially fewer side effects, as it's easier for patients to stick to a once-daily schedule. Additionally, the use of Envarsus XR may provide more stable drug levels, which is crucial for preventing organ rejection.

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

Research has shown that Envarsus XR, a once-daily extended-release form of tacrolimus and one of the treatment options in this trial, is effective for kidney transplant recipients. Studies have found it to be as safe and effective as the twice-daily version, making it a promising choice for maintaining kidney health post-transplant.

Another treatment option in this trial involves taking tacrolimus twice a day, along with other medications like mycophenolate mofetil (MMF) and steroids. This regimen has been linked to excellent survival rates for both patients and their transplanted kidneys. Clinical data supports its effectiveness in preventing organ rejection and maintaining patient health. Both treatment options in this trial have strong track records, helping patients live healthier lives after their transplant. ^{1 2 4 6 7}

Who Is on the Research Team?

Santhi Voora, MD

Principal Investigator

University of Southern California

Are You a Good Fit for This Trial?

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 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 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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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 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 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 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 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]

Citations

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

Management of kidney transplant recipients for primary ... The mean half-life in renal transplant recipients is variable according to formulation, but has been reported to be 18.8 h, 38 h, and 48.4 h ...

2. hhs.texas.gov hhs.texas.gov/sites/default/files/documents/oct-2023-durb-agenda-item3h.pdf

Immunosuppressants, Oral Therapeutic Class Review (TCR) The safety and efficacy of tacrolimus ER (Astagraf XL, Envarsus XR) in pediatric kidney transplant patients less than 16 years of age has ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10893541/

Off-Label Immunosuppressant Drugs in Solid Organ ... This update was based on the results from a non-interventional observational study providing real-world evidence of effectiveness. Since that ...

4. 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.

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

Clinical Data | ENVARSUS XR® (tacrolimus extended- ... ENVARSUS XR has been studied across multiple kidney transplant recipient types, including de novo patients, stable patients converting from other tacrolimus ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2015/206406Orig1s000MedR.pdf

206406Orig1s000 - accessdata.fda.gov In de novo kidney transplant patients who received ENVARSUS XR starting dose of 0.17 mg/kg/day achieved higher than recommended target tacrolimus trough ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4801790/

Overview of extended release tacrolimus in solid organ ... Both tacrolimus formulations have demonstrated comparable steady-state systemic tacrolimus exposure in de novo kidney and liver transplant recipients. The ...