SIMPLE: Simplified IMmunosuppressive Protocol Utilizing Low Dose EnvarsusXR
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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 Design
Arms and Interventions
| 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:
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:
|
| Active Comparator: Once-daily Regimen Once-daily regimen of Envarsus, azathioprine plus methylprednisolone or prednisone. |
Drug: Once-daily envarsus XR
Within 48 hours of transplantation, Envarsus XR (0.13mg/kg/day) will be administered once 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:
Drug: Azathioprine
Azathioprine (1-3 mg/kg) will be administered once a day.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival [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.
- To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival [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.
- To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival [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.
Secondary Outcome Measures
- Renal allograft function [Every month, for a duration of 12 months]
Estimated glomerular filtration rate (eGFR)
- Proteinuria [Every month, for a duration of 12 months]
Urinalysis
- Donor-specific antibodies (DSA) [3, 6, and 12 months]
Donor-specific anti-HLA antibodies, with a MFI (mean fluorescence intensity) >1000, measured by flow cytometry/Luminex-based assay
- Cytomegalovirus (CMV) [3, 6, and 12 months]
CMV PCR
- Liver Function [3, 6, and 12 months]
Alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase
- Gastrointestinal side effects [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.
- Dyspepsia and quality of life [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.
- Tremor [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
- Perception of quality of life [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.
- Cancer [3, 6, and 12 months]
Incidence of cancers
- Diabetes [3, 6, and 12 months]
Incidence of new onset diabetes measured by HgbA1c
- Electrolytes [3, 6, and 12 months]
Dose of magnesium, potassium and phosphorus needed to replete electrolytes
- Adverse Events [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.
- Dose changes [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.
- BK Viremia [3, 6, 12 months]
BK quantitative serum assay
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Southern California | Los Angeles | California | United States | 90033 |
Sponsors and Collaborators
- University of Southern California
- Veloxis Pharmaceuticals
Investigators
- Principal Investigator: Santhi Voora, MD, University of Southern California
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Prescribing information
- User's Manual for the Medical Outcomes Study (MOS) Core Measures of Health-Related Quality of Life
Publications
- Dalal P, Shah G, Chhabra D, Gallon L. Role of tacrolimus combination therapy with mycophenolate mofetil in the prevention of organ rejection in kidney transplant patients. Int J Nephrol Renovasc Dis. 2010;3:107-15. Epub 2010 Aug 4.
- Kulich KR, Madisch A, Pacini F, Piqué JM, Regula J, Van Rensburg CJ, Ujszászy L, Carlsson J, Halling K, Wiklund IK. Reliability and validity of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire in dyspepsia: a six-country study. Health Qual Life Outcomes. 2008 Jan 31;6:12. doi: 10.1186/1477-7525-6-12.
- Park SI, Felipe CR, Pinheiro-Machado PG, Garcia R, Fernandes FB, Casarini DE, Tedesco-Silva H Jr, Medina-Pestana JO. Tacrolimus pharmacokinetic drug interactions: effect of prednisone, mycophenolic acid or sirolimus. Fundam Clin Pharmacol. 2009 Feb;23(1):137-45. doi: 10.1111/j.1472-8206.2008.00644.x.
- Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord. 2005 Sep;11(6):367-73.
- HS-18-00513