Primary endpoint
All time points for study endpoints are measured relative to patient randomisation (day 0). The primary variable is the C/D ratio measured at 12 weeks. C/D ratio is being measured in this study as a surrogate for tacrolimus bioavailability (i.e. systemic exposure per mg of drug) and will be calculated according to the formula in Fig. Calculation of C/D ratio. In this formula, “C” represents the trough level measured in a blood sample collected immediately prior to drug dosing on the day of a trial visit (A centralised measurement of the 12-week tacrolimus blood trough level at the University Hospital Regensburg will be used to calculate C/D ratio for the primary endpoint.During the controlled treatment phase (first 12 weeks post-randomisation), tacrolimus should be dosed by the investigator to reach and maintain whole blood trough concentrations within the general reference range of 3–12 ng/ml. For every randomised patient, a narrower target range (with an interval of 3 ng/ml) within the wider reference range of 3–12 ng/ml is to be defined at all times and continually reviewed/revised based on clinical circumstances. The first target range is to be set prospectively by the investigator and documented in the eCRF at baseline to enable analysis of the pharmacokinetic endpoints. Since the frequency of trough level measurement directly influences pharmacokinetic endpoints, each trial centre aims to follow the minimum schedule of trough level measurement outlined in Fig. Tac measurements. Minimum schedule of tacrolimus trough level measurementsC/D ratio tends to fluctuate during the first weeks and months after transplantation. Twelve weeks post-randomisation (visit 7) has therefore been chosen for timing of the primary endpoint because the overall metabolic situation in patients is expected to be stable by this time. Also, at 12 weeks, the influence of concomitant immunosuppressive agents that may affect C/D ratio should be less pronounced. Corticosteroids are often concomitantly administered with tacrolimus and are allowed as non-investigational medication products (NIMP) in the EnGraft study. Since they share some common metabolic and transporter pathways with tacrolimus, higher steroid doses and rapid steroid tapering during the early post-transplant period may interfere with tacrolimus metabolism and destabilise the C/D ratio [