Simplified IMmunosuppressive Protocol Utilizing Low Dose EnvarsusXR

Kidney Transplantation Clinical Trial

— SIMPLE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04773392
• Other study ID #: HS-18-00513
• Status: Recruiting
• Phase: Phase 4
• Start date: November 23, 2021
• Est. completion date: February 2025

Study information

• Verified date: December 2023
• Source: University of Southern California
• Contact: Melissa Ramos, BSN
• Phone: 323-442-7983
• Email: Melissa.Ramos[@]med.usc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: February 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Kidney Transplant Rejection
• Kidney Transplantation

Intervention

Drug:
• Twice-daily Tacrolimus
Within 48 hours of transplantation, immediate release tacrolimus (IRT) (0.1 mg/kg /day) will be administered twice a day.
• Once-daily envarsus XR
Within 48 hours of transplantation, Envarsus XR (0.13mg/kg/day) will be administered once a day.
• 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.
• 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.
• 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.
• Azathioprine
Azathioprine (1-3 mg/kg) will be administered once a day.

Locations

Country	Name	City	State
United States	University of Southern California	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
University of Southern California	Veloxis Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (4)

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. doi: 10.2147/ijnrd.s7044. Epub 2010 Aug 4. — View Citation

Kulich KR, Madisch A, Pacini F, Pique JM, Regula J, Van Rensburg CJ, Ujszaszy 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. — View Citation

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. — View Citation

Troster 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. doi: 10.1016/j.parkreldis.2005.05.009. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival	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
Primary	To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival	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
Primary	To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival	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	Renal allograft function	Estimated glomerular filtration rate (eGFR)	Every month, for a duration of 12 months
Secondary	Proteinuria	Urinalysis	Every month, for a duration of 12 months
Secondary	Donor-specific antibodies (DSA)	Donor-specific anti-HLA antibodies, with a MFI (mean fluorescence intensity) >1000, measured by flow cytometry/Luminex-based assay	3, 6, and 12 months
Secondary	Cytomegalovirus (CMV)	CMV PCR	3, 6, and 12 months
Secondary	Liver Function	Alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase	3, 6, and 12 months
Secondary	Gastrointestinal side effects	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
Secondary	Dyspepsia and quality of life	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
Secondary	Tremor	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
Secondary	Perception of quality of life	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
Secondary	Cancer	Incidence of cancers	3, 6, and 12 months
Secondary	Diabetes	Incidence of new onset diabetes measured by HgbA1c	3, 6, and 12 months
Secondary	Electrolytes	Dose of magnesium, potassium and phosphorus needed to replete electrolytes	3, 6, and 12 months
Secondary	Adverse Events	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
Secondary	Dose changes	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
Secondary	BK Viremia	BK quantitative serum assay	3, 6, 12 months

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