Purpose: The H2304 (NCT00622869) study compared the efficacy and safety of concentration-controlled everolimus (EVR) to eliminate or to reduce tacrolimus (TAC) vs standard TAC (TAC-C) in de novo liver transplant recipients (LTxR). Here, we present the 24 month (M) results.
Methods: In this 24M, multicenter, open-label study, 719 de novo LTxR were randomized (1:1:1) on day 30±5 to receive EVR (C0 3-8ng/mL) with reduced TAC (C0 3-5ng/mL; EVR+rTAC) or EVR (C0 6-10ng/mL) with TAC withdrawal (TAC-WD) at M4 or TAC-C (C0 6-10ng/mL), all with steroids. Composite efficacy failure rate (treated BPAR [tBPAR], graft loss, or death) and its components, renal function (eGFR; MDRD4 formula) and safety were assessed at M24. The TAC-WD arm was prematurely terminated due to higher rate of acute rejection (EVR+rTAC vs TAC comparison is presented).
Results: At M24, the composite efficacy failure rate was comparable between EVR+rTAC and TAC-C (10.3% vs 12.5%; difference: -2.2% [97.5% CI: -8.8%, 4.4%]). BPAR was significantly lower and less severe with EVR+rTAC vs TAC-C (table). At M24, EVR+rTAC maintained superior renal function vs TAC-C (difference in eGFR change from randomization: 6.66 mL/min/1.73m2 [97.5% CI: 1.9, 11.42], p=0.0018 for ITT population and 8.69 mL/min/1.73m2 [97.5% CI: 4.01, 13.36], p<0.0001 for on-treatment patients). In the EVR+rTAC group, 29.8% patients discontinued study drug due to adverse events compared with 21.5% in the TAC-C group. No new safety signals were identified during the study.
Conclusion: Early TAC reduction facilitated by EVR at 1M in LTxR maintains antirejection efficacy and leads to superior renal function vs standard TAC.
|Efficacy variables, n (KM %) ITT population||EVR+rTAC (N=245)||TAC-C (N=243)||p value|
|Composite efficacy failure (tBPAR, graft loss or death)||24 (10.3)||29 (12.5)||0.452|
|Graft loss or death||17 (7.3)||14 (6.2)||0.638|
|Graft loss||9 (3.9)||7 (3.2)||0.661|
|Death||12 (5.2)||10 (4.4)||0.701|
|tBPAR||11 (4.8)||18 (7.7)||0.203|
|BPAR||14 (6.1)||30 (13.3)||0.010|
|Severity of BPAR (RAI score), n (%)|
|Mild (4-5)||9 (3.7)||10 (4.1)||–|
|Moderate (6-7)||0 (0)||8 (3.3)||–|
|Severe (8-9)||0 (0)||2 (0.8)||–|
Fung, J.: Grant/Research Support, Sanofi, Novartis. Jones, R.: Speaker’s Bureau, Roche Australia, Other, Novartis, Advisory Board, Speaker, Drug Trial PI, Jansen Cilag Australia, Advisory Board, Speaker, Drug Trial PI. Neuhaus, P.: Grant/Research Support, Astellas, Novartis. Dong, G.: Employee, Novartis. Lopez, P.: Employee, Novartis. Junge, G.: Employee, Novartis. Nevens, F.: Grant/Research Support, Ipsen, Roche, MSD, Boston Scientific.
To cite this abstract in AMA style:Fung J, Chavin K, Moysyuk Y, Orloff S, Yantorno S, Jones R, Neuhaus P, Dong G, Lopez P, Junge G, Nevens F. Everolimus-Facilitated Reduction of Tacrolimus in De Novo Liver Transplant Recipients Achieves Comparable Overall Efficacy with Fewer Biopsy-Proven Acute Rejections Versus Standard Tacrolimus: 24-Month Results of a Randomized Trial [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/everolimus-facilitated-reduction-of-tacrolimus-in-de-novo-liver-transplant-recipients-achieves-comparable-overall-efficacy-with-fewer-biopsy-proven-acute-rejections-versus-standard-tacrolimus-24-mont/. Accessed May 7, 2021.
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