Clinical trial NCT04773392: Simplified IMmunosuppressive Protocol Utilizing Low Dose EnvarsusXR
Official title: SIMPLE Study: A Prospective and Randomized Trial of a Simplified Immunosuppressive Protocol Utilizing Low Dose EnvarsusXR
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Kidney Transplantation
Kidney Transplant Rejection
Keywords: tacrolimus
envarsus XR
kidney transplant
rejection
immunosuppressive agents
renal transplant
Lead sponsor: University of Southern California
Sponsor class: OTHER
Collaborators: name: Veloxis Pharmaceuticals
First posted: 2021-02-26
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is an open-label, randomized, prospective clinical trial. Patients will be screened prior to surgery and randomized 1:1 to each arm.
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival
timeFrame: 3 months
measure: To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival
timeFrame: 6 months
measure: To compare the composite incidence of biopsy proven acute rejection, graft survival and patient survival
timeFrame: 12 months
Secondary outcomes:
measure: Renal allograft function
timeFrame: Every month, for a duration of 12 months
measure: Proteinuria
timeFrame: Every month, for a duration of 12 months
measure: Donor-specific antibodies (DSA)
timeFrame: 3, 6, and 12 months
measure: Cytomegalovirus (CMV)
timeFrame: 3, 6, and 12 months
measure: Liver Function
timeFrame: 3, 6, and 12 months
measure: Gastrointestinal side effects
timeFrame: 3, 6, and 12 months
measure: Dyspepsia and quality of life
timeFrame: 3, 6, and 12 months
measure: Tremor
timeFrame: 3, 6, and 12 months
measure: Perception of quality of life
timeFrame: 3, 6, and 12 months
measure: Cancer
timeFrame: 3, 6, and 12 months
measure: Diabetes
timeFrame: 3, 6, and 12 months
measure: Electrolytes
timeFrame: 3, 6, and 12 months
measure: Adverse Events
timeFrame: 3, 6, and 12 months
measure: Dose changes
timeFrame: 3, 6, and 12 months
measure: BK Viremia
timeFrame: 3, 6, 12 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
Study officials:
affiliation: University of Southern California
name: Santhi Voora, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
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.
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