Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal

Condition(s) targeted: Kidney Transplantation

Intervention: Kidney Biopsy (Procedure); Rapamune (sirolimus/rapamycin) (Drug); Tacrolimus (Drug)

Phase: Phase 4

Status: Enrolling by invitation

Sponsored by: University at Buffalo

Official(s) and/or principal investigator(s):
Mark R Laftavi, MD, FACS, Principal Investigator, Affiliation: University at Buffalo School of Medicine Deparment of Surgery
Oleh G. Pankewycz, MD, Principal Investigator, Affiliation: University at Buffalo

Current therapy to prevent organ rejection relies on the use of calcineurin inhibitors either cyclosporine or tacrolimus. Although these agents have been very successful in preventing early acute rejection, this success has not translated into improved long-term kidney transplant function. One of the important factors that leads to premature kidney transplant failure is chronic allograft nephropathy (CAN). CAN is characterized by progressive interstitial fibrosis or "scarring", vascular wall thickening, and finally glomerular sclerosis leading to slow progressive loss of kidney function. Calcineurin inhibitors have been shown to play an important role in the pathogens of CAN. Renal transplant recipients in whom calcineurin inhibitors are discontinued enjoy better and longer kidney function. Therefore, immunosuppressive strategies are being designed with the intention of withdrawing calcineurin inhibitors. The purpose of this trial is to test if tacrolimus can be safely substituted by sirolimus (Rapamycin) and this substitution will yield improved renal function, less CAN and better graft survival rates over the first year.

Official title: Phase 4 Study: Comparison of Myfortic and Early Rapamycin Conversion vs. Low-Dose Tacrolimus in Preventing Acute Rejection and Chronic Allograft Fibrosis: A Protocol Biopsy Directed Approach

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

equivalent patient and graft survival at one year

either equivalent or improved GFR (Cockcroft-Gault) at one year in the Rapamycin group

lack of a significant difference in clinical or subclinical acute rejections between the 2 treatment arms

equivalent time to first biopsy proven acute rejection

improved histology at 12 months in the Rapamycin group

composite end point of clinical and subclinical rejection free graft and patient survival

Secondary outcome:

improved blood pressure control requiring fewer anti-hypertensive medications in the Rapamycin group

improved glucose control at one year in the Rapamycin group

improved compliance with medications in the Rapamycin group

improved quality of life measures in the Rapamycin group

equivalent rates of infectious complications

equivalent rates of readmission to the hospital and length of stay over the 12 months

equivalent lipid control using statin therapy

equivalent dose changes of immunosuppression regimen

Detailed description: The purpose of this study is to determine if tacrolimus can be safely lowered to potentially non-nephrotoxic levels or discontinued completely in favor of Rapamycin 3 months after kidney transplantation. In this study, all patients will be maintained on full-dose (720 mg BID) mycophenolate sodium (Myfortic) to ensure adequate immunosuppression. In addition, we will compare the immunosuppressive regimens of Rapamune/mycophenolate sodium/Prednisone to Low-Dose Prograf/ mycophenolate sodium /Prednisone for their long-term effects on renal function, cardiovascular risk factors, subclinical rejection and chronic allograft fibrosis. We also plan to examine the clinical benefit of protocol biopsies. The first protocol biopsy would occur at the time of implantation. This would provide an assessment of the state of the donor kidney. The severity of donor disease would provide a baseline to which all subsequent biopsies can be compared. The second protocol biopsy would be performed at the time of tacrolimus withdrawal. Patients found to have subclinical rejection on this biopsy would not undergo tacrolimus withdrawal but may benefit from increased immunosuppression. The protocol biopsy would provide an additional level of safety ensuring that only "low-risk" (histologically) patients undergo tacrolimus withdrawal. A third biopsy would be performed one year after transplantation. Renal allograft tissue would be examined for the presence of progressive fibrosis or persistent subclinical rejection both of which lead to graft failure. The efficacy of tacrolimus withdrawal can be assessed using both clinical and pathologic criteria. A third aim of this trial is to examine whether changes in immunosuppressive therapy leads to differential expression of immunological markers or serum mediators such as cytokines. Recent studies suggest that, in vitro, thymoglobulin induces the generation of "regulatory" cells. This study will examine the in vivo relevance of this novel observation. In addition, we will measure the circulatory mediators of renal fibrosis to examine if the two treatment arms differ in their effects on such cytokine/growth factors. Blood samples will be collected and the PBMC will be analyzed by FACS for their composition and the presence of cell surface antigens that may reflect a state of immunological regulation or "suppression". Tissue samples will be analyzed by immunohistochemistry for the presence of immunologically relevant cellular subtypes such as CD4/CD25 regulatory T cells. Serum samples will be collected and analyzed for cytokine or growth factor expression.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. All patients receiving their first renal allograft transplant will be considered eligible for study 2. Patients receiving both living and cadaveric donors will be eligible Exclusion Criteria: 1. If less than 18 years of age 2. Severe hyperlipidemia 3. If pregnant or cannot comply with proper birth control during the study 4. Recipients of kidney together with another solid organ or bone marrow transplant 5. Patients receiving any investigational medications or participating in a clinical trial 6. Patients receiving a second or third renal allograft 7. PRA > 30% 8. Active infections 9. Chronic antiarrhythmic therapy for ventricular arrhythmia 10. Malignancy except for basal cell carcinoma 11. HIV 12. ANC count < 1,000/ mm3, Platelet count < 100,00/mm3 13. Fasting triglycerides > 400 mg/dl and cholesterol > 300 mg/dl 14. HCV-positive, HBVSAg-positive, HBVCoreAb-positive and HBVSAntibody negative or HCV/HBV co-infected patients 15. Breastfeeding women

Buffalo General Hospital Multi-Organ Transplant Department, Buffalo, New York 14203, United States

Related publications:

Oberbauer R, Kreis H, Johnson RW, Mota A, Claesson K, Ruiz JC, Wilczek H, Jamieson N, Henriques AC, Paczek L, Chapman J, Burke JT; Rapamune Maintenance Regimen Study Group. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study. Transplantation. 2003 Jul 27;76(2):364-70.

Ruiz JC, Campistol JM, Grinyó JM, Mota A, Prats D, Gutiérrez JA, Henriques AC, Pinto JR, García J, Morales JM, Gómez JM, Arias M. Early cyclosporine a withdrawal in kidney-transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions. Transplantation. 2004 Nov 15;78(9):1312-8.

Mota A, Arias M, Taskinen EI, Paavonen T, Brault Y, Legendre C, Claesson K, Castagneto M, Campistol JM, Hutchison B, Burke JT, Yilmaz S, Häyry P, Neylan JF; Rapamune Maintenance Regimen Trial. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant. 2004 Jun;4(6):953-61.

Larson TS, Dean PG, Stegall MD, Griffin MD, Textor SC, Schwab TR, Gloor JM, Cosio FG, Lund WJ, Kremers WK, Nyberg SL, Ishitani MB, Prieto M, Velosa JA. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant. 2006 Mar;6(3):514-22.

Salvadori M, Holzer H, de Mattos A, Sollinger H, Arns W, Oppenheimer F, Maca J, Hall M; ERL B301 Study Groups. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant. 2004 Feb;4(2):231-6.

Starting date: January 2008
Last updated: May 8, 2009