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Daily low-dose prednisolone to prevent relapse of steroid-sensitive nephrotic syndrome in children with an upper respiratory tract infection: PREDNOS2 RCT

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Martin T. Christian, Nicholas Ja Webb, Rebecca L. Woolley, Nafsika Afentou, Samir Mehta, Emma Frew, Elizabeth A. Brettell, Adam R. Khan, David V. Milford, Detlef Bockenhauer, Moin A. Saleem, Angela S. Hall, Ania Koziell, Heather Maxwell, Shivaram Hegde, Eric R. Finlay, Rodney D. Gilbert, Caroline Jones, Karl McKeever, Wendy Cook & 1 more Natalie Ives

Original languageEnglish
Pages (from-to)i-93
Number of pages94
JournalHealth technology assessment (Winchester, England)
Volume26
Issue number3
DOIs
Published1 Jan 2022

Bibliographical note

Funding Information: The research reported in this issue of the journal was funded by the HTA programme as project number 11/129/261. The contractual start date was in October 2012. The draft report began editorial review in January 2020 and was accepted for publication in June 2021. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. Funding Information: T he PREDNOS2 investigators would like to thank the NIHR HTA programme for funding this trial. Funding Information: The PREDNOS2 trial was sponsored by the Central Manchester University Hospitals NHS Foundation Trust (subsequently renamed the Manchester University NHS Foundation Trust) and the University of Birmingham (RG_12-188). The MHRA clinical trial authorisation reference was 21761/0281/001-0001. The EudraCT number was 2012-003476-39. Funding Information: Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 3. See the NIHR Journals Library website for further project information. Funding Information: Declared competing interests of authors: Martin T Christian is a member of the International Pediatric Nephrology Association Clinical Practice Guideline Group for Steroid Sensitive Nephrotic Syndrome (2020–present). Nicholas JA Webb reports personal fees from Novartis Pharma AG (Basel, Switzerland) outside the submitted work. Nafsika Afentou has received a grant from the National Institute for Health Research (NIHR) for research unrelated to this report (NIHR300440). Emma Frew has received grants from NIHR (nine in the 36 months prior to publication: NIHR300773, 03/164/51, 17/92/39, 14/185/13, 15/184/14, RP-PG-0618-20008, NIHR203012, RP-DG-1215-10002 and NIHR CDF 2015 08 013), UK Research and Innovation (London, UK) (BB/V004832/1) and Zhejiang Yongning Pharmaceutical Co., Ltd (Taizhou, The People’s Republic of China) for research unrelated to this report. Elizabeth A Brettell reports grants from NIHR during the conduct of the study. Other than the grants received for the PREDNOS (PREDnisolone in NephrOtic Syndrome) studies (reference 08/53/31), other NIHR grants received include grants for the ECUSTEC (ECUlizumab in Shiga-Toxin producing Escherichia Coli Haemolytic Uraemic Syndrome) trial (reference 14/48/43) and the GHD (Growth Hormone Deficiency) Reversal Study (reference NIHR127468). Caroline Jones sits on the Paediatric Medicines Expert Advisory Group for the Medicines and Healthcare products Regulatory Agency (January 2017–present). Funding Information: This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health and Social Care. Funding Information: Declared competing interests of authors: Martin T Christian is a member of the International Pediatric Nephrology Association Clinical Practice Guideline Group for Steroid Sensitive Nephrotic Syndrome (2020?present). Nicholas JA Webb reports personal fees from Novartis Pharma AG (Basel, Switzerland) outside the submitted work. Nafsika Afentou has received a grant from the National Institute for Health Research (NIHR) for research unrelated to this report (NIHR300440). Emma Frew has received grants from NIHR (nine in the 36 months prior to publication: NIHR300773, 03/164/51, 17/92/39, 14/185/13, 15/184/14, RP-PG-0618-20008, NIHR203012, RP-DG-1215-10002 and NIHR CDF 2015 08 013), UK Research and Innovation (London, UK) (BB/V004832/1) and Zhejiang Yongning Pharmaceutical Co., Ltd (Taizhou, The People?s Republic of China) for research unrelated to this report. Elizabeth A Brettell reports grants from NIHR during the conduct of the study. Other than the grants received for the PREDNOS (PREDnisolone in NephrOtic Syndrome) studies (reference 08/53/31), other NIHR grants received include grants for the ECUSTEC (ECUlizumab in Shiga-Toxin producing Escherichia Coli Haemolytic Uraemic Syndrome) trial (reference 14/48/43) and the GHD (Growth Hormone Deficiency) Reversal Study (reference NIHR127468). Caroline Jones sits on the Paediatric Medicines Expert Advisory Group for the Medicines and Healthcare products Regulatory Agency (January 2017?present).This work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people?s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone?s privacy,andit?s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/ data-citation. Publisher Copyright: © 2022, NIHR Journals Library. All rights reserved.

King's Authors

Abstract

Background: Most children with steroid-sensitive nephrotic syndrome have relapses that are triggered by upper respiratory tract infections. Four small trials, mostly in children already taking maintenance corticosteroid in countries of different upper respiratory tract infection epidemiology, showed that giving daily low-dose prednisone/prednisolone for 5–7 days during an upper respiratory tract infection reduces the risk of relapse. Objectives: To determine if these findings were replicated in a large UK population of children with relapsing steroid-sensitive nephrotic syndrome on different background medication or none. Design: A randomised double-blind placebo-controlled trial, including a cost-effectiveness analysis. Setting: A total of 122 UK paediatric departments, of which 91 recruited patients. Participants: A total of 365 children with relapsing steroid-sensitive nephrotic syndrome (mean age 7.6 ± 3.5 years) were randomised (1: 1) according to a minimisation algorithm based on background treatment. Eighty children completed 12 months of follow-up without an upper respiratory tract infection. Thirty-two children were withdrawn from the trial (14 prior to an upper respiratory tract infection), leaving a modified intention-to-treat analysis population of 271 children (134 and 137 children in the prednisolone and placebo arms, respectively). Interventions: At the start of an upper respiratory tract infection, children received 6 days of prednisolone (15 mg/m 2) or an equivalent dose of placebo. Main outcome measures: The primary outcome was the incidence of first upper respiratory tract infection-related relapse following any upper respiratory tract infection over 12 months. The secondary outcomes were the overall rate of relapse, changes in background treatment, cumulative dose of prednisolone, rates of serious adverse events, incidence of corticosteroid adverse effects, change in Achenbach Child Behaviour Checklist score and quality of life. Analysis was by intention-to-treat principle. The cost-effectiveness analysis used trial data and a decision-analytic model to estimate quality-adjusted life-years and costs at 1 year, which were then extrapolated over 16 years. Results: There were 384 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the prednisolone arm, and 407 upper respiratory tract infections and 82 upper respiratory tract infection-related relapses in the placebo arm. The number of patients experiencing an upper respiratory tract infection-related relapse was 56 (42.7%) and 58 (44.3%) in the prednisolone and placebo arms, respectively (adjusted risk difference –0.024, 95% confidence interval –0.14 to 0.09; p = 0.70). There was no evidence that the treatment effect differed when data were analysed according to background treatment. There were no significant differences in secondary outcomes between treatment arms. Giving daily prednisolone at the time of an upper respiratory tract infection was associated with increased quality-adjusted life-years (0.9427 vs. 0.9424) and decreased average costs (£252 vs. £254), when compared with standard care. The cost saving was driven by background therapy and hospitalisations after relapse. The finding was robust to sensitivity analysis. Limitations: A larger number of children than expected did not have an upper respiratory tract infection and the sample size attrition rate was adjusted accordingly during the trial. Conclusions: The clinical analysis indicated that giving 6 days of daily low-dose prednisolone at the time of an upper respiratory tract infection does not reduce the risk of relapse of steroid-sensitive nephrotic syndrome in UK children. However, there was an economic benefit from costs associated with background therapy and relapse, and the health-related quality-of-life impact of having a relapse. Future work: Further work is needed to investigate the clinical and health economic impact of relapses, interethnic differences in treatment response, the effect of different corticosteroid regimens in treating relapses, and the pathogenesis of individual viral infections and their effect on steroid-sensitive nephrotic syndrome. Trial registration: Current Controlled Trials ISRCTN10900733 and EudraCT 2012-003476-39.

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