A multicentre randomised controlled trial to assess the safety and efficacy of adding rituximab to standard of care in treating acute antibody-mediated rejection in kidney transplantation (Transplant Antibody-mediated Rejection: Guiding Effective Treatments-1 (TAR:GET-1))

INTERVENTION: Product Name: Rituximab Pharmaceutical Form: Concentrate and solvent for concentrate for solution for infusion INN or Proposed INN: Anti‐CD20 monoclonal antibody CAS Number: 0174722‐31‐7 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ Product Name: Methylprednisolone Pharmaceutical Form: INN or Proposed INN: Corticosteroid CAS Number: 83‐43‐2 Product Name: IVIg (high dose) Pharmaceutical Form: INN or Proposed INN: immunoglobulin CAS Number: 9007‐83‐4 Product Name: IVIg (low dose) Pharmaceutical Form: INN or Proposed INN: immunoglobulin CAS Number: 9007‐83‐4 CONDITION: Renal Transplant antibody‐mediated rejection ; MedDRA version: 20.0 Level: PT Classification code 10023439 Term: Kidney transplant rejection System Organ Class: 10021428 ‐ Immune system disorders Therapeutic area: Body processes [G] ‐ Immune system processes [G12] PRIMARY OUTCOME: Main Objective: The trial will test two different treatment options currently used to treat acute antibody‐mediated rejection (aAMR) in kidney transplant patients in the UK. Trial participants will be allocated randomly (decided by chance using a computer) to receive one of the two treatments. To find out how the trial treatments compare, we will measure kidney transplant function over time. Each participant will be followed up for a minimum of 4 years. The time from the date of randomisation to the date of transplant failure (measured as return to dialysis treatment or function test failure) will be measured in both groups. Primary end point(s): Allograft survival, defined as the duration from the date of randomisation to the date of starting dialysis dependency or date of eGFR (estimated Glomerular Filtration Rate) <15 mL/min/1.73 m2, whichever occurs first. Secondary Objective: • As well as determining how many transplants are still working in each of the treatment arms, we will also determine how well the remaining transplants are functioning. This will be analysed by assessing the level of function using a blood test and testing for protein leak in the urine over time. ; • The effect the two different treatments has on the level of detectable antibody against in the transplant (donor specific antibody) will also be measured. ; • It is also important to know how safe these treatments are. Therefore, we need to compare how common and frequent certain side effects occur with each treatment.; • Because these treatments are expensive, we next need to analyse whether they provide value for money for the NHS (and the taxpayer). The way in which we measure value for money includes how well people feel and how active they are.; Timepoint(s) of evaluation of this end point: Allograft survival will be determined at 4 years.; Interim analyses will also be made for DMEC review.; SECONDARY OUTCOME: Secondary end point(s): 1. Allograft function measured by serum creatinine, estimated glomerular filtration rate (CKD‐EPI) and proteinuria (urinary ptotein:creatinine ratio) at 1, 3, 6, and 12 months post‐randomisation and then annually until 4 years; 2. Donor specific antibody (DSA) positivity, number of DSA and mean fluorescence index (immunodominant); 3. Safety, determined by adverse event reporting; 4. Health‐related quality of life, assessed by EQ‐5D‐5L/EQ‐5D‐Y questionnaire; 5. Economic analysis of cost per quality‐adjusted life year gained from the perspective of the NHS; Timepoint(s) of evaluation of this end point: These will be determined at 4 years.; Interim analyses will also be made for DMEC review. INCLUSION CRITERIA: 1. Willing and able to give written informed consent by patient aged 16 years and over; or by a parent or legal guardian for patients who are under 16 years old 2. Aged 5 years old or older, at the time of consent 3. A diagnosis of acute AMR as defined by: a. The presence of =1 donor specific antibodies (DSA) b. An adequate transplant biopsy (=7 glomeruli and =1 artery) with histological features consistent with active AMR with no evidence of chronicity as defined by the Banff histological classification of allograft pathology: i. If C4d positive (2 or 3): • v score =1 and/or • g score =1 and/or • thrombotic microangiopathy and/or • ptc score =1 • or if co‐existent cellular rejection, a g score of =1 OR ii. If C4d negative (0 or 1): • microcirculation inflammatory score (g + ptc) =2