Title: A UK multicentre randomised controlled trial to determine the efficacy of treatments for acute antibody mediated rejection in renal transplantation
Funder: Department of Health and Social Care

Abstract: Kidney transplantation is the best treatment for patients with End-Stage Kidney Disease (ESKD). It improves patient survival, quality of life, and considerably reduces the healthcare cost of ESKD (1-13). Most transplants fail over time (average 8 to 15 years) (14). Rejection is a leading cause for such failure (16). The worst kind of rejection, acute Antibody Mediated Rejection (AAMR) affects 7% of patients within the first year after transplantation (5). There are no current recognised treatment recommendations for AAMR, due to the absence of evidence on the safety and effectiveness of existing treatments from randomised trials. Consequently, treatments vary greatly among UK transplant centres (21). Treatments for AAMR has been identified as a leading research priority by the NIHR JLA and the UK Kidney Research Consortium. We now propose a trial of the most promising emerging treatments for AAMR. DESIGN An open-label, 2-arm randomised controlled trial to evaluate the effectiveness of current therapies used to treat acute AMR. SETTING Adult and paediatric renal transplant centres in the UK. TARGET POPULATION Renal transplant recipients with acute AMR. INCLUSIONS Biopsy-proven kidney transplant acute AMR EXCLUSIONS 1) ABO incompatible transplant 2) HLA incompatible transplant and previous rituximab 3) Active infection or malignancy 4) Pregnancy TECHNOLOGIES BEING ASSESSED The addition of Rituximab (SOCR) to standard of care, versus standard of care alone (SOC). SOC consists of plasma exchange (PEX), intravenous immunoglobulin (IVIg) and glucocorticoids. RANDOMISATION: 1:1 OUTCOME MEASURES The primary efficacy end point is allograft survival at 4 years. An internal feasibility analysis will be performed at 12 and 21 months. Feasibility will depend on recruitment and acceptability of the protocol. Secondary endpoints: 1) Cost effectiveness of SOCR from the perspective of the NHS 2) Adverse event analyses: SAE, AEI 3) Kidney transplant function (eGFR, proteinuria) 4) Health related quality of life (EQ5D) SAMPLE SIZE The trial will recruit 170 patients over 40 months. We estimate a control arm 4-year allograft survival of less than 30%, based on contemporary UK data on 160 cases of acute AMR (64). Using Cox regression to assess 4-year allograft survival, the trial will have 95% power to detect an increase in allograft survival from 35% to 60% in the investigational arm compared to SOC. TIMETABLE Recruitment will require 40 months. The trial will conclude after 88 months. EXPERTISE IN THE TEAM: The trial team includes expertise in design, conduct and delivery of interventional trials (TFH, EW, JW, CC), trials in transplantation and treatment of acute AMR (MW, SK, RB, NT, SG, DG, LH, MRC), paediatric transplantation (SM), histological diagnosis (CR), patient perspective (CC and FC), health economics (EW) and trials statistics with particular reference to MAMS design (JW). EW, TFH and JW have experience of HRQoL data in trials.

Lay abstract: KIDNEY TRANSPLANTS DON’T LAST INDEFINITELY The best treatment for kidney failure is a kidney transplant. Having a transplant is better than dialysis, keeping patients healthier, happier and more independent. Transplants also cost the NHS much less than dialysis. Unfortunately, most kidney transplants fail, typically after between 8 and 15 years. REJECTION IS TO BLAME Without medication, the body rejects transplanted kidneys. Even with modern medicines, rejection may happen and is a leading cause of transplant failure. The worst kind of rejection results from antibodies against the transplant. This is called acute antibody mediated rejection (AAMR). AAMR happens to 1 in every 14 patients within 12 months of a transplant. When AAMR happens, the chances of the kidney still working 4 years later are only 3/10. BEST TREATMENT UNKOWN There have been no good trials in AAMR to test how safe or effective the treatments are that are currently being used in the NHS. There are some promising treatments, but whether you receive them for AAMR depends on which transplant centre you go to. They are also expensive and have side effects. Trials to test them are urgently needed. PLUGGING THE EVIDENCE GAP We will conduct a trial in UK patients with AAMR to test the most promising two treatments. We have designed this trial with input from patients, the UK Kidney Research Consortium, leading transplant specialists, and experts in clinical trials. STUDY DESIGN All patients with AAMR will be asked to participate. Those who agree will receive one of two treatments, allocated randomly (decided by chance using a computer). The treatments are: 1) Standard of Care (SOC) includes the most widely used treatments: plasma exchange, IVIg and steroids. 2) SOC plus Rituximab (SOCR) MEASURING WHICH IS BEST We will need to enrol 170 patients (85 in each treatment group). This should take 40 months. To find out how the trial treatments compare, we will measure kidney transplant function over time. Each participant will be followed up for 4 years. After the last participant has been in the trial for 4 years, we will compare the number of kidney transplants still working between the two groups. 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. CAN WE AFFORD THE STUDY? Kidney Research UK has already awarded £750,000 for this trial. We are now asking the NIHR for the rest. We have designed the study to be as efficient as possible. We will also conduct ‘interim analysis’ after 21 months, less than a quarter into the study. This means we look at how recruitment is going, how promising the new treatments look, and how safe they appear to be. THE TEAM Our team includes a kidney transplant patient, trials experts, transplant specialists, a statistician and a health economist. The study is supported by a national expert trials group (UKRTN).

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL