The Use of Rituximab In the treatment of Nephrotic Glomerulonephritis (TURING)

RESEARCH QUESTION Does the addition of rituximab to standard of care delay relapse in patients with Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS)? BACKGROUND MCD and FSGS are rare diseases that cause nephrosis. Patients suffer with debilitating oedema, and are at increased risk of infection and venous thromboembolism. Standard of care consists of high dose glucocorticoids, with associated morbidity including weight gain, diabetes, infection and osteoporosis. Patients require frequent hospital visits, hence these diseases carry a high socioeconomic burden. This is particularly high in FSGS, where patients with uncontrolled disease progress to end stage kidney disease (ESKD), at an annual cost of £26,300 for hospital haemodialysis. Better treatments are needed for MCD/FSGS. Rituximab is a monoclonal B cell depleting antibody, which is licensed for other autoimmune diseases, including ANCA vasculitis which is also a cause of ESKD. Rituximab has been shown to be safe and effective in delaying relapse in children with relapsing MCD/FSGS, but due to a lack of RCT data, is not funded by NHSE for adults. AIMS AND OBJECTIVES Primary objective: to assess the effect of rituximab on time to relapse in patients with MCD/FSGS. Secondary objectives: to assess the effect of rituximab on (i) NHS and societal resource use and hence cost to assess the effect of rituximab on safety and on secondary measures of efficacy (ii) Health status METHODS 112 patients with new presentation or relapsing MCD/FSGS will be recruited. They will be randomised to receive rituximab (2 x 1g within 4 weeks of randomisation, followed by 1g at 6 months) or placebo. All patients will receive standard of care treatment with prednisolone, with a protocolised dosing regimen. Trial follow up visits will align with standard of care clinic visits. Data collection will include proteinuria, serum albumin, renal function and QoL. The primary endpoint will be time from partial remission to relapse. Follow up will continue until the last patient recruited has completed 24 months of follow up, with a final common close out for all patients. An open label extension study will be open to patients in the placebo arm who reach the primary endpoint of relapse. TIMELINES FOR DELIVERY The protocol will be finalised by the end of February 2019, with HRA, REC and ethics approval obtained concurrently. The first site will open for recruitment in June 2019, with 2 sites then being activated each month. A feasibility analysis after 18 months will assess recruitment, with a target of 45 patients assuming site opening has also achieved target. Recruitment will complete by the second quarter end in 2021 with trial close by second quarter end 2023. The primary report will be completed by second quarter end in 2024. ANTICIPATED IMPACT AND DISSEMINATION The following outputs will be presented at UK Renal Association Kidney Week, and at international meetings. Reports will be submitted to leading international scientific journals for open access publication. All manuscripts will be deposited in the University of Cambridge open access repository. i. Trial protocol ii. The report of the efficacy and safety of rituximab in MCD/FSGS. iii. Economic Evaluation – including within-trial, decision model, and VoI analyses iv. Outcome and cost of the open-label extension study – reported as a prospective cohort study with longitudinal cost of illness analysis and outcomes.