Simplified IMmunosuppressive Protocol Utilizing Low Dose EnvarsusXR (SIMPLE)

December 4, 2023 updated by: Santhi Voora, University of Southern California

SIMPLE Study: A Prospective and Randomized Trial of a Simplified Immunosuppressive Protocol Utilizing Low Dose EnvarsusXR

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Estimated)

80

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90033
        • Recruiting
        • University of Southern California
        • Contact:
        • Principal Investigator:
          • Santhi Voora, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Twice-daily Regimen
Twice-daily regimen of immediate release tacrolimus, mycophenolate mofetil (MMF)/mycophenolic acid (MPA) plus daily methylprednisolone or prednisone.
Drug: Twice-daily Tacrolimus
Within 48 hours of transplantation, immediate release tacrolimus (IRT) (0.1 mg/kg /day) will be administered twice a day.
Drug: Induction Immunosuppression with Basiliximab or Rabbit Anti Thymoglobulin (rATG)
Induction immunosuppression with Basiliximab or Rabbit Anti Thymoglobulin (rATG) per protocol. The dose of Basiliximab will be a standard of two 20 mg doses and total rATG will not exceed 6 mg/kg.
Drug: Methylprednisolone, prednisone
Methylprednisolone intraoperatively (500mg) and immediately post transplantation (200mg on post operative day (POD) #1, 150mg on POD#2, 100mg on POD#3) then oral prednisone (50mg on POD #4, 20mg on POD #5). Oral prednisone will be tapered down to a minimal dose of 5mg within 6 weeks post transplantation.
Other Names:
  • Steroids
Drug: Mycophenolate mofetil (MMF) or Mycophenolic acid (MPA)
Mycophenolate mofetil (MMF) (up to 1000mg) or Mycophenolic acid (MPA) (up to 720mg) will be administered twice a day.
Other Names:
  • Twice a day anti-metabolite
Active Comparator: Once-daily Regimen
Once-daily regimen of Envarsus, azathioprine plus methylprednisolone or prednisone.
Drug: Induction Immunosuppression with Basiliximab or Rabbit Anti Thymoglobulin (rATG)
Induction immunosuppression with Basiliximab or Rabbit Anti Thymoglobulin (rATG) per protocol. The dose of Basiliximab will be a standard of two 20 mg doses and total rATG will not exceed 6 mg/kg.
Drug: Methylprednisolone, prednisone
Methylprednisolone intraoperatively (500mg) and immediately post transplantation (200mg on post operative day (POD) #1, 150mg on POD#2, 100mg on POD#3) then oral prednisone (50mg on POD #4, 20mg on POD #5). Oral prednisone will be tapered down to a minimal dose of 5mg within 6 weeks post transplantation.
Other Names:
  • Steroids
Drug: Once-daily envarsus XR
Within 48 hours of transplantation, Envarsus XR (0.13mg/kg/day) will be administered once a day.
Drug: Azathioprine
Azathioprine (1-3 mg/kg) will be administered once a day.
Other Names:
  • Once a day anti-metabolite

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival
Time Frame: 3 months
Biopsies will be performed for unexplained rise in serum creatinine or proteinuria and the development of donor specific antibodies. Biopsies will be assessed by a pathologist using standard Banff classification of renal allograft pathology. Graft loss will be defined as return to chronic dialysis or graft removal.
3 months
To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival
Time Frame: 6 months
Biopsies will be performed for unexplained rise in serum creatinine or proteinuria and the development of donor specific antibodies. Biopsies will be assessed by a pathologist using standard Banff classification of renal allograft pathology. Graft loss will be defined as return to chronic dialysis or graft removal.
6 months
To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival
Time Frame: 12 months
Biopsies will be performed for unexplained rise in serum creatinine or proteinuria and the development of donor specific antibodies. Biopsies will be assessed by a pathologist using standard Banff classification of renal allograft pathology. Graft loss will be defined as return to chronic dialysis or graft removal.
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Renal allograft function
Time Frame: Every month, for a duration of 12 months
Estimated glomerular filtration rate (eGFR)
Every month, for a duration of 12 months
Proteinuria
Time Frame: Every month, for a duration of 12 months
Urinalysis
Every month, for a duration of 12 months
Donor-specific antibodies (DSA)
Time Frame: 3, 6, and 12 months
Donor-specific anti-HLA antibodies, with a MFI (mean fluorescence intensity) >1000, measured by flow cytometry/Luminex-based assay
3, 6, and 12 months
Cytomegalovirus (CMV)
Time Frame: 3, 6, and 12 months
CMV PCR
3, 6, and 12 months
Liver Function
Time Frame: 3, 6, and 12 months
Alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase
3, 6, and 12 months
Gastrointestinal side effects
Time Frame: 3, 6, and 12 months
GI side effects will be assessed by the Gastrointestinal Symptoms Rating Scale (GSRS) is a 15 item questionnaire addressing reflux, abdominal pain, indigestion, diarrhea and constipation. The GSRS has a seven-point graded Likert-type scale where 1 represents absence of troublesome symptoms and 7 represents very troublesome symptoms.
3, 6, and 12 months
Dyspepsia and quality of life
Time Frame: 3, 6, and 12 months
The Quality of Life in Reflux and Dyspepsia (QOLRAD) is a 25 item instrument depicting problems with emotions, vitality, sleep, eating/drinking, and physical/social functioning in adult patients with reflux disease. The questions are rated on a seven-point graded Likert scale; lower values indicate a more severe impact on daily functioning.
3, 6, and 12 months
Tremor
Time Frame: 3, 6, and 12 months
Tremor will be assessed by Quality of life in Essential Tremor Questionnaire, (QUEST) a 30-item scale developed specifically for patients with essential tremor to measure items impacting perceived quality of life (QOL). The items are rated on a five-point scale (score 0-4), corresponding to the frequency (never, rarely, sometimes, frequently, always) with which tremor was perceived to currently impact a function or to be associated with various feelings and attitudes
3, 6, and 12 months
Perception of quality of life
Time Frame: 3, 6, and 12 months
The Short Form (36) Healthy Survey (SF-36) is a multi-purpose survey designed to capture adult patients' perceptions of their own health and well-being.Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability.
3, 6, and 12 months
Cancer
Time Frame: 3, 6, and 12 months
Incidence of cancers
3, 6, and 12 months
Diabetes
Time Frame: 3, 6, and 12 months
Incidence of new onset diabetes measured by HgbA1c
3, 6, and 12 months
Electrolytes
Time Frame: 3, 6, and 12 months
Dose of magnesium, potassium and phosphorus needed to replete electrolytes
3, 6, and 12 months
Adverse Events
Time Frame: 3, 6, and 12 months
An adverse event can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use the product, whether or not related to the product.
3, 6, and 12 months
Dose changes
Time Frame: 3, 6, and 12 months
Frequency of dose changes made in Envarsus, tacrolimus and MMF/MPA. Dosage changes will be adjusted for Tacrolimus drug levels as per protocol. MMF/MPA will be adjusted depending on gastrointestinal tolerability and bone marrow suppression.
3, 6, and 12 months
BK Viremia
Time Frame: 3, 6, 12 months
BK quantitative serum assay
3, 6, 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Southern California

Collaborators

Veloxis Pharmaceuticals

Investigators

  • Principal Investigator: Santhi Voora, MD, University of Southern California

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 23, 2021

Primary Completion (Estimated)

February 1, 2025

Study Completion (Estimated)

February 1, 2025

Study Registration Dates

First Submitted

February 15, 2021

First Submitted That Met QC Criteria

February 25, 2021

First Posted (Actual)

February 26, 2021

Study Record Updates

Last Update Posted (Estimated)

December 5, 2023

Last Update Submitted That Met QC Criteria

December 4, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HS-18-00513

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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