Simplified IMmunosuppressive Protocol Utilizing Low Dose EnvarsusXR (SIMPLE)

University of Southern California

Status and phase: Terminated; Phase 4

Conditions: Kidney Transplantation; Kidney Transplant Rejection

Treatments: Drug: Once-daily envarsus XR; Drug: Methylprednisolone, prednisone; Drug: Twice-daily Tacrolimus; Drug: Azathioprine; Drug: Induction Immunosuppression with Basiliximab or Rabbit Anti Thymoglobulin (rATG); Drug: Mycophenolate mofetil (MMF) or Mycophenolic acid (MPA)

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT04773392

HS-18-00513

Details and patient eligibility

About

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.

Full description

While short-term graft outcomes in kidney transplantation have improved, this requires adherence to a complex medication regimen. The current twice-daily immunosuppressive regimen, immediate release tacrolimus and mycophenolate mofetil/mycophenolic acid, has reduced rejection rates significantly, but frequently cause neurologic and gastrointestinal side effects which impact recipient quality of life. These side effects often require dose adjustments and studies have shown inferior outcomes when multiple changes are made to the immunosuppressive regimen. Furthermore, patients taking twice-daily medications have poorer compliance and yet adherence to these medications is critical to mitigate the risk of allograft rejection. Acute and chronic rejection are important causes of graft failure and patient survival.

Immediate release (IR) tacrolimus based immunosuppressive regimens have become the standard of care at most US centers. With the introduction of a once-daily tacrolimus formulation, kidney transplant recipients can now be on a combination regimen (EnvarsusXR and azathioprine) that permits all immunosuppressive medications to be taken once a day instead of twice . Previous studies suggest that therapeutic goals with EnvarsusXR may be achieved at a lower dose than the currently recommended dose. This once a day medication schedule has the potential to simplify the immunosuppressive regimen by reducing adverse side effects and facilitating compliance.

The investigators seek to demonstrate that a once-daily regimen, including EnvarsusXR and azathioprine, will be at least equally effective with respect to acute rejection, graft and patient survival as compared to the standard, twice-daily, immediate release tacrolimus and mycophenolate mofetil/mycophenolic acid. The investigators will also assess graft function, medication complications and side effects in each arm.

Enrollment: 20 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• De- Novo Kidney transplant patients between 18 and 85 years old
• Cold ischemia time (CIT) < 24 hours for 3-6 HLA mismatches between donor and recipient and CIT >24 hours for HLA mismatch of less than 3 between donor and recipient
• Most recent pre-transplant cPRA (calculated panel reactive antibody) ≤ 20%

Exclusion criteria

• Repeat kidney transplant recipients
• cPRA >20%
• rATG (rabbit anti-thymocyte globulin) induction >6mg/kg at time of induction
• Crossmatches deemed positive by accepting physician
• Presence of pre-formed anti-HLA (anti-Human Leukocyte Antigen) DSA (Donor-Specific Antibody) as defined by MFI (mean fluorescence intensity) approaching 3000 using flow cytometry/Luminex-based, specific anti-HLA antibody testing.
• Receipt of desensitization protocols
• History of skin cancer
• Recipient of multi-organ or dual kidney transplants
• For any condition, in which the investigator's opinion makes the subject unsuitable for study

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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20 participants in 2 patient groups

Twice-daily Regimen

Active Comparator group

Description:

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

Treatment:

Drug: Mycophenolate mofetil (MMF) or Mycophenolic acid (MPA)

Drug: Induction Immunosuppression with Basiliximab or Rabbit Anti Thymoglobulin (rATG)

Drug: Twice-daily Tacrolimus

Drug: Methylprednisolone, prednisone

Once-daily Regimen

Active Comparator group

Description:

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

Treatment:

Drug: Induction Immunosuppression with Basiliximab or Rabbit Anti Thymoglobulin (rATG)

Drug: Azathioprine

Drug: Methylprednisolone, prednisone

Drug: Once-daily envarsus XR