Perioperative immunosuppressive Management after Liver Transplantation in long-term follow-up – a randomized clinical trial

• Applicant: Privatdozent Dr. Dennis Eurich
• Subject Area: General and Visceral Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518501032

Immunosuppression (IS) after liver transplantation (LT) is adapted individually to the comorbidity for rejection prophylaxis continuously as a balancing act according to the principle "as little as possible and as much as necessary" mostly as a combination with a calcineurin inhibitor and an antiproliferative substance such as mycophenolate or everolimus. In the long-term course after LT, patients have to undergo surgery once on average. Due to the feared wound healing disorders that may result from antiproliferative agents, IS is switched perioperatively to e.g. monotherapy with tacrolimus (Tac) in a center-specific manner without reliable evidence, and thus may permanently disrupt the balancing act without benefit. The liver as a transplanted organ is immunologically privileged, and it is very likely that in many cases no immunosuppression is needed at all in the long-term course. This spontaneous tolerance and the propensity for it can be exploited for surgical interventions. Not least at the suggestion of patients who discontinued their IS in many scenarios and who take their IS with excellent discipline, the present study idea has emerged. The planned multicenter, prospective, randomized non-inferiority trial aims to clarify the significance of perioperative IS conversion in patients in long-term follow-up after LT. The hypothesis raised is a lack of benefit of perioperative IS conversion and risk increase for the occurrence of adverse effects compared to IS pause. For this purpose, a total of 252 patients from ten German transplant centers will be randomized in a 1:1 ratio into two arms. In the intervention arm, IS will be paused without replacement and reintroduced 2-4 weeks after surgery according to the default setting. In the control arm includes all center-specific approaches regarding perioperative IS conversion or IS continuation. The primary endpoint concerns the recording of perioperative complications including graft dysfunction measured by the Clavien-Dindo-based comprehensive complication index (CCI) as 90-day morbidity. Secondary endpoints include occurrence of acute rejection, IS-associated adverse events, waiting time for surgery, costs incurred, and inpatient length of stay. The primary objective of the study is to demonstrate the noninferiority of the concept of perioperative pausing of tailored IS with the aid of the not unlikely tolerance or long time to occurrence of eventual rejection compared with the conversion or continuation approach. A hypothetical demonstration of the noninferiority of pausing tailored IS would significantly simplify perioperative management, avoid numerous useless and possibly hazardous steps in the follow-up of LT patients, and also generate evidence for the perioperative management of immunosuppression in this context.

• DFG Programme: Clinical Trials
• Co-Investigator: Dr. Ramin Raul Ossami Saidy