Improving Transplant Opportunities for Patients who are Sensitized (ITOPS): Protocol for a Feasibility, Randomized, Controlled, Phase III Clinical Trial

• Background: Kidney transplantation offers a better quality of life and a clear survival advantage compared to long-term dialysis. However, rates of transplantation are low for highly sensitized patients (HSP) who have a broad specificity of human leucocyte antigen (HLA) specific antibodies. This is because the presence of pre-formed HLA Donor Specific Antibodies can result in hyperacute rejection and is an immunological veto to transplantation. The proportion of eligible donors therefore decreases with increasing sensitization, resulting in increased waiting time prior to transplantation. This study aims to assess the efficacy of a combination of B cell depletion and proteasome inhibition, together with antibody removal and steroids, to reduce HLA antibodies in HSP, predicted to improve rates of transplantation, and to determine the feasibility of conducting a future definitive trial. • Methods: ITOPS is a multi-center, randomized parallel, non-blinded, controlled phase III feasibility trial. The participants will be allocated in a 1:1 ratio to either the trial intervention (rituximab followed by 1-2 cycles of plasmapheresis, bortezomib and dexamethasone) or control group (no intervention). • Discussion: The primary outcome is the proportion of patients achieving an absolute reduction in sensitization (calculated reaction frequency, cRF) of at least 10% at 12 weeks following their last intervention, compared to the control group. Secondary outcomes include recruitment and transplantation rates, durability of change and absolute percentage change in cRF, and acceptability of the intervention. We will proceed to development of a larger trial if at least 50% of the participants in the intervention arm achieve an absolute reduction in cRF of a minimum of 10% at 12 weeks following their last intervention. If the proportion is Trial Registration: International Standard Randomized Controlled Trial Number ISRCTN66441193 https://doi.org/10.1186/ISRCTN66441193