Envarsus, a novel once-daily, MeltDose formulation of tacrolimus (Tac), has greater bioavailability, a more consistent concentration profile, noninferior efficacy and similar safety and with lower total daily dose (TDD) vs. traditional twice-daily Tac (Prograf). From a Phase 3, double-blind, double-dummy, multicenter trial of de novo kidney transplant recipients (KTR) randomized to once-daily Envarsus (n=268) or twice-daily Prograf (n=275), we explored the relationship between Tac trough level as a time-dependent covariate and treatment failure (graft loss, death, biopsy-proven acute rejection, or lost to follow-up). Treatment failure rates were similar between Envarsus (18.3%) and Prograf (19.6%); however, events occurred later for Envarsus-treated KTR (at a mean of 101.7 days posttransplant) vs. Prograf (mean: 83.3 days). Kaplan-Meier analysis showed comparable efficacy throughout the study (figure). Within the first 3 months posttransplant, when KTR have the greatest rejection risk, treatment failure rates were LCP-Tacro: 10.4% and Prograf: 14.2%, P=0.124. In days 2-4, TDD was higher for Envarsus (˜12mg) vs. Prograf (˜8mg), reflecting the higher Envarsus starting dose (0.17mg/kg vs. 0.10mg/kg for Prograf). Tac trough levels were notably greater in the Envarsus group vs. the Prograf group in the first 2 weeks after dosing; thereafter, trough levels were similar. Higher Tac trough level was significantly (P<0.001) associated with a decreased risk for treatment failure (Hazard ratio: 0.85; 95% CI 0.82-0.95). These findings support improved bioavailability of Envarsus results in a dose-sparing effect and permits rapid attainment of therapeutic levels. These results confirm the hypothesis that low levels of Tac pose an increased risk of treatment failure in de novo KTR.Figure: No Caption available.DISCLOSURES:Rostaing, L.: Other, Chiesi, advisory board. Budde, K.: Grant/Research Support, AiCuris, Astellas, BmT GmbH, Bristol-Myers Squibb, speaker's fees, honoraria, travel expenses, Chiesi, Hexal, Novartis, Roche, Pfizer, Siemens, speaker's fees, honoraria, travel expenses, Veloxis, speaker's fees, honoraria, travel expenses, Other, Bristol-Myers Squibb, Chiesi, Effimune, Hexal,, consultant, Novartis, Pfizer, Veloxis, consultant. Bunnapradist, S.: Grant/Research Support, Veloxis, Genentech, Novartis, Speaker's Bureau, Novartis, Other, Veloxis, Advisory Board.