Two-year results of multicenter phase III trials on the effect of the addition of sirolimus to cyclosporine-based immunosuppressive regimens in renal transplantation

Randomized clinical trials conducted over 24 months and including nearly 1300 renal transplant patients compared the efficacy and safety of two dose levels of sirolimus versus azathioprine (United States) or placebo (Global) comparators administered with a cyclosporine (CsA) and prednisone (Pred) baseline regimen. Analysis of 24-month data revealed that patients in the 5 mg/d sirolimus groups experienced a significant delay in the onset and reduction in the incidence of acute rejection episodes compared with azathioprine (Aza) or placebo groups (P = .02/P = .001). Graft and patient survival rates and also the occurrence of transplant-related infections, lymphoproliferative disorders, or malignancies were similar among all treatment arms. Between 12 and 24 months, patients treated with 2 mg/d sirolimus displayed relatively stable mean serum creatinine values, namely 1.9-1.8 mg/dL for the US and 1.8-1.8 mg/dL for the Global (P = NS) studies, which remained higher than those of the comparators. Both 5 mg/d groups showed an increase in mean serum creatinine during this interval, which was significantly higher than the value in both comparators at 24 months. Both sirolimus groups showed persistently elevated triglyceride levels compared with Aza-treated patients at month 24. The Global trial showed a less-pronounced difference in mean fasting triglyceride values compared with placebo. Data from both trials demonstrate that the addition of sirolimus to a CsA-Pred treatment regimen yielded a durable immunosuppressive effect associated with a progressive resolution of adverse side effects over time except for hyperlipidemia, which required continued countermeasure therapy.