Modifying tacrolimus related toxicity after liver transplantation. A randomized controlled trial comparing Envarsus® and Advagraf® in de novo liver transplant recipients.

Chronic use of tacrolimus is associated with significant side effects including
new onset diabetes after transplantation (NODAT), renal impairment,
hypertension, hyperlipidemia and tremor and other neurotoxic traits. It is
known that toxicity of tacrolimus is (partly) related to higher peak serum
blood concentrations in the first year after transplantation. Reducing peak
levels without reducing effective inhibition of the immune response could
therefore theoretically attenuate the toxic effects of tacrolimus. Envarsus®, a
prolonged release formulation of tacrolimus which gives less fluctuation of
whole-blood tacrolimus concentrations and requires lower dosage for similar
systemic tacrolimus exposure has the potential to lower the toxic effects of
tacrolimus and decrease the amount of metabolic side effects, as compared to
the current standard, Advagraf®.

To investigate whether Envarsus® leads to a significant reduction in new onset
diabetes, chronic kidney disease and new onset hypertension.

Randomized controlled two-arm phase 4 intervention trial comparing Envarsus®
with the current standard treatment Advagraf® after liver transplantation.

At discharge post transplantation patients will be initiated on prolonged
release tacrolimus, which, according to randomization, will either be standard
Advagraf® or Envarsus®.

The study resembles our standard clinical practice in that recipients are
always converted from an immediate release tacrolimus (i.e. Prograft®) to an
extended release formulation (previously exclusively Advagraf®) at hospital
discharge. Furthermore, the study visit schedule is an exact copy of our
regular outpatient visit schedule post-transplantation and does not include any
invasive interventions. All blood draws scheduled in this study are part of
routine care.
Patients will have AUC measurements of tacrolimus concentrations.
Throughout the study participants will be closely (monthly) monitored for
adequate tacrolimus exposure. As both tacrolimus formulations are approved for
this indication and the active drug on both formulations is the same, this
study is considered a low risk study. The anticipated benefit of this study is
that it may lead to lowering of the metabolic side effects, nefrotoxicity and
neurotoxicity of long term tacrolimus treatment. Thus, we believe that the
benefit-risk assessment for this study is favourable.