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 (MMFCC) dosing with a fixed‐dose regimen in 720 kidney recipients. Patients received either (A) MMFCC and reduced‐level calcineurin inhibitor (MMFCC/CNIRL); (B) MMFCC and standard‐level CNI (MMFCC/CNISL); or (C) fixed‐dose MMF and CNISL (MMFFD/CNISL). 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, MMFCC with low‐dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMFFD, indicating potential utility of MMFCC in CNI‐sparing regimens. In this randomized trial, concentration‐controlled dosing of mycophenolate mofetil with reduced doses of calcineurin inhibitors was not inferior to standard dosing.