The ORION Study: Comparison of Two Sirolimus‐Based Regimens versus Tacrolimus and Mycophenolate Mofetil in Renal Allograft Recipients

Safety and efficacy of two sirolimus (SRL)‐based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher‐than‐expected biopsy‐confirmed acute rejections (BCARs), was sponsor‐terminated; therefore, Group 2 two‐year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One‐ and 2‐year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1‐ and 2‐year modified intent‐to‐treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One‐year post hoc analysis of new‐onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between‐group malignancy rates were similar. The SRL‐based regimens were not associated with improved outcomes for kidney transplantation patients.

[1]  J. O’Shea.  Faculty Opinions recommendation of Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. , 2012 .

[2]  F. Berthoux,et al.  Thymoglobulin Induction and Sirolimus Versus Tacrolimus in Kidney Transplant Recipients Receiving Mycophenolate Mofetil and Steroids , 2010, Transplantation.

[3]  H. Meier‐Kriesche,et al.  Mammalian Target of Rapamycin Inhibitor Dyslipidemia in Kidney Transplant Recipients , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  A. Webster,et al.  Sirolimus is associated with new-onset diabetes in kidney transplant recipients. , 2008, Journal of the American Society of Nephrology : JASN.

[5]  M. Ghoneim,et al.  Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients. , 2008, Journal of the American Society of Nephrology : JASN.

[6]  P. Halloran,et al.  Reduced exposure to calcineurin inhibitors in renal transplantation. , 2007, The New England journal of medicine.

[7]  E. Thervet,et al.  Sirolimus Versus Cyclosporine in Kidney Recipients Receiving Thymoglobulin®, Mycophenolate Mofetil and a 6‐Month Course of Steroids , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[8]  A. Novick,et al.  Kidney Transplantation With Sirolimus and Mycophenolate Mofetil–Based Immunosuppression: 5-Year Results of a Randomized Prospective Trial Compared to Calcineurin Inhibitor Drugs , 2007, Transplantation.

[9]  A. Novick,et al.  Kidney Transplantation With Sirolimus and Mycophenolate Mofetil–Based Immunosuppression: 5-Year Results of a Randomized Prospective Trial Compared to Calcineurin Inhibitor Drugs , 2007 .

[10]  G. Martínez-Mier,et al.  Living related kidney transplantation without calcineurin inhibitors: initial experience in a Mexican center. , 2006, Transplantation.

[11]  A. Webster,et al.  Target of Rapamycin Inhibitors (Sirolimus and Everolimus) for Primary Immunosuppression of Kidney Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Trials , 2006, Transplantation.

[12]  T. Larson,et al.  Complete Avoidance of Calcineurin Inhibitors in Renal Transplantation: A Randomized Trial Comparing Sirolimus and Tacrolimus , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  R. Oberbauer.  Calcineurin Inhibitor Withdrawal from Sirolimus‐Based Therapy in Kidney Transplantation: A Systematic Review of Randomized Trials , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  D. Goldfarb,et al.  The natural history of chronic allograft nephropathy. , 2005, The Journal of urology.

[15]  S. Head,et al.  De Novo Kidney Transplantation Without Use of Calcineurin Inhibitors Preserves Renal Structure and Function at Two Years , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  J. Morales,et al.  Pilot Randomized Study of Early Tacrolimus Withdrawal from a Regimen with Sirolimus Plus Tacrolimus in Kidney Transplantation , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[17]  G. Russ,et al.  EARLY CYCLOSPORINE WITHDRAWAL FROM A SIROLIMUS-BASED REGIMEN RESULTS IN BETTER RENAL ALLOGRAFT SURVIVAL AND RENAL FUNCTION AT 48 MONTHS AFTER TRANSPLANTATION , 2004, Transplant international : official journal of the European Society for Organ Transplantation.

[18]  K. Baboolal.  A phase III prospective, randomized study to evaluate concentration-controlled sirolimus (rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients1,2 , 2003, Transplantation.

[19]  S. Jensik,et al.  Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months1 , 2003, Transplantation.

[20]  L. Gesualdo,et al.  Early withdrawal of cyclosporine A improves 1-year kidney graft structure and function in sirolimus-treated patients , 2003, Transplantation.

[21]  F. Schena,et al.  Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination1, 2 , 2002, Transplantation.

[22]  A. Novick,et al.  Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine1 , 2002, Transplantation.

[23]  M. Pescovitz,et al.  Sirolimus and mycophenolate mofetil for calcineurin-free immunosuppression in renal transplant recipients. , 2001, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[24]  R. Oberbauer,et al.  Sirolimus Allows Early Cyclosporine Withdrawal in Renal Transplantation Resulting in Improved Renal Function and Lower Blood Pressure. , 2001 .

[25]  A. Macdonald.  A WORLDWIDE, PHASE III, RANDOMIZED, CONTROLLED, SAFETY AND EFFICACY STUDY OF A SIROLIMUS/CYCLOSPORINE REGIMEN FOR PREVENTION OF ACUTE REJECTION IN RECIPIENTS OF PRIMARY MISMATCHED RENAL ALLOGRAFTS , 2001, Transplantation.

[26]  Barry D Kahan,et al.  Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study , 2000, The Lancet.

[27]  J. Squifflet,et al.  Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. , 2000, Transplantation.

[28]  B. Julian,et al.  Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. , 1999, Transplantation.

[29]  H. Meier‐Kriesche,et al.  Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. , 1999, Transplantation.

[30]  R. Calne,et al.  Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. , 1999, Transplantation.

[31]  Bennett Wm.  Insights into chronic cyclosporine nephrotoxicity. , 1996 .

[32]  W. Bennett.  Insights into chronic cyclosporine nephrotoxicity. , 1996, International journal of clinical pharmacology and therapeutics.