Pivotal Phase Iii Multicenter, Randomized, Blinded Trial of Sirolimus Versus Azathioprine in Combination With Cyclosporine and Prednisone in Primary Renal Transplants

68 Purpose: This study sought to establish the immunosuppressive efficacy and adverse reaction profile of addition of sirolimus (rapamycin, Rapamune, RAPA) versus azathioprine (AZA) to potentiate the acute rejection prophylaxis conferred by a cyclosporine (CsA)-prednisone (Pred) baseline regimen. Methods: 719 primary cadaveric (n=466) or mismatched living-donor (n=253) renal transplant recipients were randomly assigned to receive RAPA 2 mg (n=284), RAPA 5 mg (n=274), or azathioprine (AZA) 2-3 mg/kg (n=161) in blinded fashion, in addition to a protocol-stipulated regimen of tapering amounts of CsA and Pred. The efficacy endpoints included acute rejection episodes (AREs), graft loss, and/or death. The adverse events in each treatment group were monitored by detailed clinical reporting and laboratory tests. Results: The demographic features of the three groups were similar. The efficacy endpoints for occurrence of AREs for RAPA 2 mg, RAPA 5 mg, and AZA groups at 6 months were 15%, 11%, and 24%, respectively (p<0.01 and p<0.001, respectively). Furthermore, the time to the first ARE was significantly shorter for the 2 mg RAPA (p=0.022) and the 5 mg RAPA (p<0.001) than for the AZA group. The need for antilymphocyte antibodies was significantly reduced at 6 months in the RAPA 2 mg (5.6%, p<0.01) and RAPA 5 mg (2.9%, p<0.001) groups versus the AZA (13%) group. While there was a graft survival (GS) advantage at 6 months for the RAPA 2 mg group (98.2%, p=0.026) compared to the RAPA 5 mg (93.4%, p=NS) and AZA (94.4%) groups, the GS rates were similar at 12 months: 94.7%, 92.7%, and 93.7%, respectively. Patient survival (PS) rates were also similar at 12 months: for the 2 mg RAPA group, 97.2%; for 5 mg, 96%; and for AZA, 94.4% (p=NS by log rank test). The RAPA groups showed a dose-related decrease in platelet count at 1 month that resolved by 4 months, as well as an increase in triglycerides and cholesterol that reached a peak at 2 months and tended to respond to countermeasure therapy. Only herpes simplex viral infections showed a significantly increased incidence (RAPA 5 mg, 8%, versus AZA, 2%, or RAPA 2 mg, 4%). Serum creatinine values were slightly but significantly higher among RAPA-treated patients. (Table)TableConclusion: Addition of RAPA potentiates the immunosuppressive efficacy of a CsA-Pred-based regimen, with only a modest penalty of infectious or toxic reactions.