Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: The opticept trial

Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed-dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and clinical endpoints of rejection and toxicity. This 2-year, open-label, randomized, multicenter trial compared the efficacy and safety of concentration-controlled MMF (MMF _CC) dosing with a fixed-dose regimen in 720 kidney recipients. Patients received either (A) MMF _CC and reduced-level calcineurin inhibitor (MMF _CC/CNI _RL); (B) MMF _CC and standard-level CNI (MMF _CC/CNI _SL); or (C) fixed-dose MMF and CNI _SL (MMF _FD/CNI _SL). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (α = 0.05) of group A versus group C for treatment failure (including biopsy-proven acute rejection [BPAR], graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p ≤ 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMF _CC with low-dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMF _FD, indicating potential utility of MMF _CC in CNI-sparing regimens.