Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged-Release Tacrolimus Regimens-The DIAMOND Study

Abstract

DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids).

Primary endpoint: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.

Keywords: calcineurin inhibitor; clinical research/practice; clinical trial; glomerular filtration rate (GFR); immunosuppressant; immunosuppression/immune modulation; liver allograft function/dysfunction; liver transplantation/hepatology; liver transplantation: split; tacrolimus.

© 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals Inc.

Figures

Figure 1

DIAMOND study design. Multicenter, randomized, open‐label, parallel‐group comparative Phase IIIb study. *0 mg–1,000 mg IV bolus corticosteroid (pre‐, intra‐, or post‐operatively) on Day 0. Arm 2 only: if the patient had not received treatment for an acute rejection episode and the last recorded trough level recorded was ≥ 5 ng/mL at Day 43, then the dose was reduced by 20–25%. HCV, hepatitis C virus; IV, intravenous; MMF, mycophenolate mofetil.

Figure 2

Patient disposition and reasons for discontinuation. Arm 1: Prolonged‐release tacrolimus (initial dose 0.2 mg/kg/day) + MMF; Arm 2: Prolonged‐release tacrolimus (initial dose 0.15–0.175 mg/kg/day) + MMF + basiliximab; Arm 3: Prolonged‐release tacrolimus (initial dose 0.2 mg/kg/day delayed until Day 5) + MMF + basiliximab. Four patients in Arm 3 had protocol violations (FAS): interruption of study medication > 7 consecutive days (two patients), SAE (one patient), and received mycophenolic acid (one patient); AEs were given as the primary reason for discontinuation by the study investigators. The types of AEs leading to discontinuation were not reported, as patients may have had multiple AEs at the time of discontinuation. AE, adverse event; FAS, full‐analysis set; mITT, modified intent to treat; MMF, mycophenolate mofetil; PPS, per‐protocol set; SAF, safety‐analysis set; SAE, serious adverse event.

Figure 3

Mean tacrolimus trough levels (a) in the first 35 days posttransplant and (b) throughout the study period, stratified by treatment arm over 24 weeks of treatment (FAS). Error bars represent standard error of mean. In Arm 3, three patients received prolonged‐release tacrolimus before Day 5. FAS, full‐analysis set; MMF, mycophenolate mofetil.

Figure 4

(a) eGFR (MDRD4) in the FAS population, and (b) Kaplan–Meier analysis of composite efficacy failure‐free survival in the mITT population, over 24 weeks of treatment. Data in Figure 4a are represented as least‐square means and error bars represent standard error of the mean. eGFR, estimated glomerular filtration rate; FAS, full‐analysis set; MDRD4, Modification of Diet in Renal Disease‐4; mITT, modified intent to treat; MMF, mycophenolate mofetil.