Liver Immunosuppression Free Trial

This is a prospective, multi-centre, phase IV, biomarker-strategy design trial with a randomised control group in which adult liver transplant recipients will undergo immunosuppression (IS) withdrawal. Immunosuppression drugs (IS) are: Tacrolimus, cyclosporine and/or mycophenolic acid, mycophenolate mofetil or azathioprine. Enrolled participants will be randomised 1:1 to either: 1) Non-Biomarker-based IS weaning (Weaning-All; Arm A); or 2) Biomarker-based IS weaning (Arm B). In participants allocated to Arm A IS will be withdrawn regardless of the result of the biomarker test. Among participants allocated to Arm B, only those found to be biomarker-positive (Arm B+, i.e. potentially tolerant) will be offered IS withdrawal, while biomarker-negative participants (Arm B-, i.e. potentially non-tolerant) will remain on their baseline maintenance IS. This will allow us to demonstrate that the biomarker is a useful test to personalise IS by offering drug withdrawal only to those participants who are likely to complete the process successfully, avoiding unnecessary rejections among those who have not developed tolerance. Comparing the outcome of IS withdrawal between arms A and B+ will provide direct evidence of the clinical usefulness of the test as a function of its predictive accuracy. We have established that for the biomarker to drive safe IS withdrawal its Positive Predictive Value should be no less than 0.80, and its sensitivity at least 070. To account for centre effects, we will use stratified randomization. Furthermore, to avoid biases, participants undergoing drug withdrawal and their physicians will be blinded to the biomarker results. Participants randomized to Arm B- will know their biomarker status, and will be maintained in the study until its termination and contribute to secondary clinical outcomes and to the evaluation of the stability of the tolerance signature. Cost and quality of life (HrQOL) assessments will be conducted alongside the trial to estimate the health-economic implications of the 2 different strategies. Furthermore, sequential biological specimens will be collected to conduct ancillary mechanistic studies. Recruitment will take place in 11 European liver transplant units (King's College Hospital, Royal Free London, Newcastle, Birmingham, Leeds, Edinburgh, Cambridge, Leuven, Hannover, Berlin and Barcelona).