Early initiation of everolimus (EVR) with reduced-exposure tacrolimus (rTAC) has been shown to maintain an efficacy and safety profile comparable to that of a standard-exposure TAC (sTAC) regimen and preserves renal function in living-donor liver transplant recipients (LDLTRs) up to 12 months post-LT. Here, we present 24-month (M) renal function outcomes from the H2307 study involving LDLTRs receiving EVR+rTAC or sTAC regimens.Methods
H2307 (NCT01888432) was a 24M, multicentre, open-label trial in which 284 adult de novo LDLTRs were randomized (1:1) on Day 30±5 post-LT to receive EVR+rTAC (EVR trough level [C0]: 3-8 ng/mL; TAC C0: 3-5 ng/mL) or sTAC (TAC C0: randomization (RND)-M4: 8-12 ng/mL; after M4: 6-10 ng/mL) regimen. Efficacy assessment at M24 was incidence of composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death in EVR+rTAC and sTAC arms. Renal assessments at M24 included estimated glomerular filtration (eGFR [MDRD4]) in overall study population and in patients with hepatocellular carcinoma (HCC). Other assessments included evaluation of proteinuria and renal adverse events (AEs) up to M24.Results
Overall results are presented in Table 1. Of 284 randomized patients, 88% in both arms completed the 24M study. At M24, 78% of patients in EVR+rTAC arm were within EVR C0 range although mean TAC C0 was below target range in sTAC arm. EVR+rTAC was non-inferior to sTAC for the primary endpoint of composite efficacy failure at M24 (9.0% vs 8.0%; P<0.001 by one-sided test for non-inferiority). In the overall population, eGFR was comparable between EVR+rTAC and sTAC (78.4 and 75.3 mL/min/1.73 m2) arms, with between-arm least square mean change from RND to M24 not significantly different in the full analysis and on-treatment populations. Among patients with HCC at LT, eGFR was significantly higher in the EVR+rTAC arm (P = 0.009). In overall population, proportion of patients with M24 eGFR ≥60 mL/min/1.73 m2 was higher in the EVR+rTAC (76.4%) vs sTAC (66.9%) arm. Although mean proteinuria and urinary protein creatinine ratio (UPCR) were significantly higher in EVR+rTAC vs sTAC arm (P<0.001), most patients in both arms remained in the low-to-mild categories for proteinuria (>80% with <0.5 g/24 h/SA) and UPCR (>70% with ≥30-<300 mg/g) at M24. Incidence of AEs and AEs leading to study drug discontinuation was comparable between arms; however, discontinuations due to renal AEs such as renal failure and renal impairment were numerically lower in EVR+rTAC vs sTAC arm (Table 2).Conclusions
At M24, early EVR initiation with rTAC in LDLTRs resulted in comparable renal function outcomes as sTAC regimen. Significantly better renal function was observed in patients with HCC on EVR+rTAC, which warrants additional analysis.