Modifying tacrolimus related toxicity after liver transplantation comparing meltdose tacrolimus (Envarsus®) and extended-release tacrolimus (Advagraf®): a multicenter randomized, controlled trial (MOTTO)

Background: The hypothesis of this study was that meltdose tacrolimus (Envarsus®) compared to extended‐release tacrolimus (Advagraf®) will result in less chronic kidney disease (CKD), newonset diabetes after transplantation (NODAT) and new‐onset hypertension. Methods: In this multicenter RCT, patients were randomized at discharge after liver transplantation (LT) in a 1:1 ratio to 1) Advagraf® (control group) or 2) Envarsus® (interventional group). The primary endpoint was a composite endpoint of any of three events at 12 months: CKD defined as eGFR <60 ml/minute/1.73 m2 for >3 months, sustained (>3 months post LT) NODAT or new‐onset hypertension. Secondary endpoints included: safety, quality of life, neurotoxicity (tremors), graft and patient survival, rejection, liver steatosis and fibrosis, pharmacokinetics and ‐dynamics. Results: A total of 106 patients were included and baseline characteristics were comparable for both groups. In the intentionto‐ treat analysis, significantly less LT recipients reached the primary endpoint at 12 months in the interventional group compared to the control group (50.9% and 71.2%, p = 0.005). No significant difference was shown between interventional group and control group in the percentage of LT recipients developing NODAT (15.1% and 21.2%, p=0.35) or new‐onset hypertension (30.2% and 36.5%, p=0.42). Significantly less LT recipients developed CKD in the interventional group compared to the control group (26.4% and 42.3%, p=0.03). The per protocol analysis showed comparable results and in addition significantly less LT recipients developed new‐onset hypertension in the interventional group compared to the control group (27.6% and 42.9%, p=0.04). In total, 95.3% (101/106) of the LT recipients developed serious adverse events (SAEs, n=156). SAEs most frequently reported: fever (23.7%), infections (10.3%) and cholangitis and bile duct obstruction (10.3%). Conclusions: After 1 year, meltdose tacrolimus (Envarsus®) results in a significant reduction in the prevalence of the composite endpoint and a significant reduction of CKD compared to extendedrelease tacrolimus (Advagraf®).