The RMR Trial. Reference Rapamune (sirolimus) Maintenance Regimen: Summary for Presentation to the Subcommittee of the Antiviral Drugs Advisory Committee on Immunosuppressive Drugs. Wyeth-Ayerst Research, 24 January 2002. Background
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Rapamune (sirolimus) Maintenance Regimen: Summary for Presentation to the Subcommittee of the Antiviral Drugs Advisory Committee on Immunosuppressive Drugs. Wyeth-Ayerst Research, 24 January 2002.
The therapeutic effect and nephrotoxicity of cyclosporine (CsA) depends on the inhibition of calcineurin. So a potent immunosuppressive without calcineurin-agonist properties could prolong the half-life of the transplanted organ and improve allograft function at all intermediate time intervals.
To assess the equivalence in the rates of graft survival at 12 months after transplantation in recipients of primary or secondary renal allografts who were receiving either continuous therapy with CsA and sirolimus (group A) or were receiving a regimen of CsA and sirolimus followed by concentration-controlled sirolimus and CsA elimination (group B).
a. Pivotal study: Non-IND, Phase III, randomized, open label, 2-part study also known as study 310.
b. Supportive RMR study: Open label, randomized, phase II study also known as study 212.
a. Study 310: A total of 430 patients were randomly assigned to group A (RAPA+CsA group; n=215) or group B (RAPA group; n=215).
b. Study 212: A total of 246 patients were enrolled in the study and randomly assigned to either Group A (RAPA+CsA) receiving sirolimus 2 mg/day or group B (RAPA) receiving concentration-controlled of sirolimus dose adjusted to whole blood trough concentration of 10–20 ng/ml.
End point: For the study 310 the primary end point was the rate of graft survival at 12 months post-transplantation (graft loss was defined as physical, functional loss, retransplantation or death). For the 212 study the primary end point was the serum creatinine level assessed by comparing levels between patients who were receiving therapy and those who were rejection-free for 6 months.
Results of the 310 and 212 studies show that the combination of sirolimus, CsA and corticosteroids in the early post-operative period (followed by a time-dependent elimination of the CsA) in combination with concentration-controlled sirolimus is a safe and effective to a long-term CsA-based immunosuppression. After a year there was significant improvement in the rates of graft survival, patient survival and reduction in acute rejection. Also the renal function improved significantly in the sirolimus, CsA and concentration-controlled siromimus group.
Renal function was significantly better in all risk groups on sirolimus than in those on cyclosporine plus sirolimus, except those who had a second transplant and those with delayed graft function.
In the RMR trial renal function was significantly better in patients treated with sirolimus.