Modifying Tacrolimus-related Toxicity After Liver Transplantation Comparing Life Cycle Pharma Tacrolimus Versus Extended-released Tacrolimus: A Multicenter, Randomized Controlled Trial.

Background: The aim of this open-label, multicenter, randomized controlled study was to investigate whether the life cycle pharma (LCP)-tacrolimus compared with the extended-release (ER)-tacrolimus formulation results in a difference in the prevalence of posttransplant diabetes, hypertension and chronic kidney disease (CKD) at 12 mo after liver transplantation. Methods: Patients were 1:1 randomized to either of the 2 tacrolimus formulations. The primary endpoint was defined as a composite endpoint of any of 3 events: sustained (>3 mo postrandomization) posttransplant diabetes, new-onset hypertension, and/or CKD, defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 for >3 m during the follow-up. Results: In total, 105 patients were included. In the intention-to-treat analysis, a statistically significant lower proportion of liver transplant recipients in the LCP-tacrolimus group reached the composite primary endpoint at 12 mo compared with the ER-tacrolimus group (50.9% [27/53], 95% confidence interval [CI], 37.9%-63.9% versus 71.2% [37/52], 95% CI, 57.7%-81.7%; risk difference: 0.202; 95% CI, 0.002-0.382; P = 0.046). No significant difference was found in the per protocol analysis. In the intention-to-treat and per protocol population, fewer liver transplant recipients in the LCP-tacrolimus group developed CKD and new-onset hypertension compared with the ER-tacrolimus group. No differences in rejection rate, graft and patient survival were found. Conclusions: A statistically significant and clinically relevant reduction in the prevalence of the composite primary endpoint was found in the LCP-tacrolimus group compared with the ER-tacrolimus group in the first year after liver transplantation with comparable efficacy.

Health-related Quality of Life and Fatigue in Liver Transplant Recipients Receiving Tacrolimus Versus Sirolimus-based Immunosuppression: Results From a Randomized Trial.

BACKGROUND: The impact of different immunosuppression regimes on the health-related quality of life (HRQoL) and the severity of fatigue in liver transplant recipients is largely unknown. We investigated the impact of a sirolimus-based regimen compared with a tacrolimus (TAC)-based regimen on the HRQoL and the severity of fatigue. METHODS: In this multicenter, open-label, randomized, controlled trial, 196 patients were randomized 90 d after transplantation to (1) once daily normal-dose TAC or (2) once daily combination therapy of low-dose sirolimus and TAC. HRQoL was measured with the EQ-5D-5L questionnaire, the EQ-visual analog scale, and the severity of fatigue questionnaire Fatigue Severity Score (FSS). The EQ-5D-5L scores were translated to societal values. We examined the HRQoL and the FSS over the course of the study by fitting generalized mixed-effect models. RESULTS: Baseline questionnaires were available for 87.7% (172/196) of the patients. Overall, patients reported the least problems in the states of self-care and anxiety/depression and the most problems in the states of usual activities and pain/discomfort. No significant differences in HrQol and FSS were seen between the 2 groups. During follow-up, the societal values of the EQ-5D-5L health states and the patient's self-rated EQ-visual analog scale score were a little lower than those of the general Dutch population in both study arms. CONCLUSIONS: The HRQoL and FSS were comparable in the 36 mo after liver transplantation in both study groups. The HRQoL of all transplanted patients approximated that of the general Dutch population, suggesting little to no residual symptoms in the long term after transplantation.

Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: a multicenter, randomized, controlled trial.

The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC.