Title: Short course daily prednisolone therapy at the time of upper respiratory tract infection in children with relapsing steroid sensitive nephrotic syndrome; the PREDNOS 2 study
Funder: Department of Health and Social Care

Abstract: Design: Phase III randomised parallel group, double-blind, placebo-controlled trial. Setting: The 13 UK Paediatric Nephrology centres, plus additional teaching hospitals and district hospitals led by Consultant Paediatricians with a special interest in Paediatric Nephrology. All of these centres are currently participating in the ongoing PREDNOS study (HTA 08/53/31). Target population: Children with relapsing steroid sensitive nephrotic syndrome (SSNS). The prevalence of SSNS was reported to be 16/100,000 children in the 1960s, though since then there has been a significant rise in the number of children of South Asian origin in the UK; these children have a sixfold increased risk of developing SSNS compared with white children. There are estimated to be more than 2000 children currently under follow-up with SSNS in the UK. Health Technologies Being Assessed: Current practice is for no change to be made to immunosuppressive therapy at the time of development of an upper respiratory tract infection (URTI). The intervention being assessed within PREDNOS 2 is a 6 day course of daily prednisolone therapy at the time of onset of URTI. Children will be randomised to intervention or control group and followed for a total of 12 months. With the onset of each URTI (strict study definition will be applied) over the 12 month study period, parents will commence either a 6 day course of daily prednisolone or continue with current therapy unchanged (current standard care), placebo being used to maintain double-blinding of the study. Measurement of cost and outcomes: Primary outcome - First URTI-related relapse of nephrotic syndrome during 12 month follow-up. Relapse is defined as 3 consecutive days of Albustix 3+ proteinuria. Secondary outcomes - rate of URTI-related and any relapse of nephrotic syndrome over the 12 month study period, cumulative dose of prednisolone received over the 12 month study period, adverse effects of prednisolone including behaviour, incidence of escalation of immunosuppressive therapy (i.e. addition of ciclosporin, tacrolimus, cyclophosphamide etc.), incidence of reduction of immunosuppressive therapy (i.e. cessation of alternate day prednisolone) and quality of life using CHU-9D and PedsQL. A formal health economic analysis will also be performed. This will take the form of a cost-effectiveness analysis based on a primary clinical outcome of cost per episode of URTI-related relapse of proteinuria. Utility-based outcomes will also be incorporated into the model allowing a secondary outcome to be cost per quality-adjusted life year (QALY) gained (based on CHU-9D values). The base case economic evaluation will adopt the NHS perspective. Sample size: A total of 360 children will be recruited into the study. This will give 80% power (alpha=0.05) to detect an absolute difference of 17.5% (i.e. 35% proportional reduction) in URTI-related relapse rate (i.e. from a base rate of 50% to 32.5%), with allowance for between up to 30% drop-out. Project timetable: Months 1-6: Study set up; Months 7-30: Subject recruitment and randomisation; Month 42: Last randomised patients final assessment; Months 43-48: Data analysis and production of final study report. Please note, PREDNOS 2 was extended to include 5 years and 2 months of recruitment and randomisation to achieve the updated target of 360 patients. Duration of other sections of the project timetable remain unchange.

Lay abstract: Steroid sensitive nephrotic syndrome (SSNS) is the commonest kidney disease of childhood. Large amounts of protein are leaked into the urine resulting in generalised oedema (swelling). Treatment is with high dose oral prednisolone, a steroid drug which is effective, though associated with a number of serious side-effects including weight gain, behavioural change, diabetes, high blood pressure, poor growth and weak bones. Another HTA funded study that we are conducting (PREDNOS) is currently investigating whether giving a longer course of prednisolone at presentation results in better long-term outcomes. Following successful initial treatment, 70-80% of children develop relapses where leakage of protein into the urine recurs. These are associated with a risk of significant complications, including infection, blood clots, high cholesterol levels and malnutrition. Treatment of relapse of nephrotic syndrome is with a further course of high dose prednisolone, further increasing the risk of side-effects. Furthermore, children are kept off school, resulting in educational impairment and parental absence from work. Around 50% of children suffer frequent relapses (4 or more per year). In this situation, attempts are made to reduce prednisolone exposure with the use of other more potent drugs e.g. ciclosporin and cyclophosphamide, which are associated with other significant side-effects. It is therefore logical to attempt to reduce the frequency of relapses. There is known to be a strong link between viral upper respiratory tract infection (URTI - the common cold) and the development of relapse of nephrotic syndrome. Three previous small, methodologically sub-optimal studies from developing nations have suggested that the use of a short course of daily prednisolone at the time of URTI reduces the rate of disease relapse. Using a double-blind placebo-controlled trial, the PREDNOS 2 study will aim to determine whether the use of such therapy effectively and safely reduces the rate of relapse of nephrotic syndrome in a large population of UK children. We will randomise 360 children with relapsing SSNS to receive either 6 days of daily prednisolone or to continue unchanged on their existing therapy (the current standard care) each time they develop an URTI over the course of 12 months. We will assess the incidence of URTI-related relapse of nephrotic syndrome in both study arms and look carefully for side-effects of treatment. Were this study to show that a short course of daily prednisolone at the time of URTI effectively and safely reduces the relapse rate, this would rapidly and significantly alter practice in the UK and globally. There are already a small number of centres who routinely increase prednisolone doses in certain patients at the time of URTI, but the majority of centres do not because of a lack of sound evidence upon which to base such practice. A reduction in the relapse rate would reduce relapse and treatment associated morbidity and hospitalisation rates and reduce parental time absent from work. We will perform a formal health economic analysis and hypothesise that the use of a short course of daily prednisolone (a cheap drug) will prove to be a highly cost effective intervention. Given the absence of high prescribing costs or licencing issues it is likely that if proved to be safe and effective, the intervention could be introduced throughout the UK very rapidly. The applicants for this study include representatives from each of the 13 UK Paediatric Nephrology centres - between us we manage the entire UK SSNS population in conjunction with local paediatricians. We have already established a network of >100 UK paediatric centres successfully recruiting to the PREDNOS study, and will use these centres for PREDNOS 2. Whilst all trials of medicinal products in children require careful ethical consideration, there are no particularly complex ethical issues; children with SSNS already receive regular courses of prednisolone therapy and the aim of the study is to determine whether overall drug exposure can be reduced. Parents of children with nephrotic syndrome have been widely consulted regarding the protocol and their representative is a study co-applicant. The study team feels very well placed to deliver the study as i] we have active participation from the entire UK paediatric nephrology community alongside an active SSNS parent group and an experienced Clinical Trials Unit, thus maximising the chances of delivering the study on time and to target, ii] the study group has an established track-record in collaborative study work (PREDNOS and other national MCRN nephrology studies), iii] much of the study infrastructure (e.g. drug supply, clinical trial unit support, health economic evaluation documentation, adverse event reporting documents, IT support etc.) is already in place through PREDNOS, iv] there are no other large studies currently recruiting in this patient population. As with all prospective clinical trials, the financial support that we are requesting from NIHR is considerable, however, we feel confident that the study offers good value for money when assessed on a cost per patient basis, and we will be minimising our administrative costs by using the same Clinical Trial Unit management team as we have used for PREDNOS. Prednisolone, the drug under investigation and the associated placebo have already been produced for PREDNOS and an extension of this order will keep drug costs to a minimum.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION