Title: The Use of Rituximab In the treatment of Nephrotic Glomerulonephritis (TURING)
Funder: Department of Health and Social Care

Abstract: THE DISEASE_x000D_ Minimal Change Disease (MCD) and Focal Segmental Glomerular Sclerosis (FSGS) are rare diseases that damage kidneys in a similar way, causing protein leakage into the urine with severe swelling of the legs and face. Serious complications can arise resulting in patients being admitted to hospital with bloods clots, infections and kidney failure which may require dialysis or kidney transplantation. MCD and FSGS are caused by an immune reaction in the body, and have identical treatments. _x000D_ _x000D_ CURRENT TREATMENT_x000D_ The medications used to treat MCD and FSGS suppress the body’s immune system. The first line treatment for these diseases is high dose steroids. These have severe side effects including weight gain and diabetes, stomach ulcers which can bleed, thinning of the bones (osteoporosis) and infections. Although steroids are effective in the majority of patients, the disease often comes back (relapses) and multiple courses of steroids are required, with some patients becoming steroid dependent and unable to stop the steroids at all. Other medications are used in these relapsing patients to try and reduce the amount of steroids they need to take, such as cyclophosphamide, mycophenolate mofetil and tacrolimus. However, these treatments are not always effective and also have severe side effects including infections, infertility and increased risk of cancer. There is therefore an urgent need for better treatments for MCD and FSGS._x000D_ _x000D_ STUDY DRUG_x000D_ One potential treatment is rituximab. There have been several clinical trials using rituximab in MCD and FSGS in children and it has been found to be good in delaying disease relapse, and in reducing the need for steroids and other toxic treatments to suppress the immune system. It is generally well tolerated by patients and has fewer side effects than current treatments. It is now funded in the NHS for children but not adults. Early reports of the use of rituximab in adults with MCD and FSGS are promising, however clinical trials of its use in adults are urgently needed to establish its effectiveness and safety in this group of patients. It is an expensive medication and we do not yet know if it is better than existing treatments for adults with MCD/FSGS. If it is more effective than current treatments, it may be cheaper in the long run by keeping patients healthier for longer and preventing hospital admissions. If it the same or worse then using it would be a waste of money and may potentially endanger patients. However, testing new treatments in MCD/FSGS is difficult as these diseases are rare, and studies need to be designed to allow as many patients as possible to participate._x000D_ _x000D_ STUDY PLAN_x000D_ We have assembled a strong team of specialists in kidney disease and clinical trials and have worked with patients' representatives to design the trial. Through the Renal Association (the National Society for specialist kidney doctors in the UK) we have set up a study group to help develop trials such as this. We have asked kidney doctors all over the UK about this proposed trial and already have doctors from 30 major hospitals in the UK interested in taking part. Having such a large number of centres involved in the trial means we should be able to recruit sufficient numbers of patients in less than 3 years. This is aided by the fact that the design of the trial means that most patients with MCD/FSGS should be able to go into the study if they wish.

Lay abstract: RESEARCH QUESTION_x000D_ Does the addition of rituximab to standard of care delay relapse in patients with Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS)?_x000D_ _x000D_ BACKGROUND_x000D_ 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. _x000D_ 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._x000D_ _x000D_ AIMS AND OBJECTIVES_x000D_ Primary objective: to assess the effect of rituximab on time to relapse in patients with MCD/FSGS. _x000D_ 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_x000D_ _x000D_ METHODS_x000D_ 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._x000D_ _x000D_ TIMELINES FOR DELIVERY_x000D_ 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._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION_x000D_ 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._x000D_ i. Trial protocol _x000D_ ii. The report of the efficacy and safety of rituximab in MCD/FSGS. _x000D_ iii. Economic Evaluation – including within-trial, decision model, and VoI analyses_x000D_ iv. Outcome and cost of the open-label extension study – reported as a prospective cohort study with longitudinal cost of illness analysis and outcomes.

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