Sixteen-week versus standard eight-week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT.



Webb, Nicholas Ja ORCID: 0000-0001-8572-5446, Woolley, Rebecca L ORCID: 0000-0001-5119-1431, Lambe, Tosin, Frew, Emma ORCID: 0000-0002-5462-1158, Brettell, Elizabeth A ORCID: 0000-0002-0669-3085, Barsoum, Emma N ORCID: 0000-0003-4386-3917, Trompeter, Richard S ORCID: 0000-0003-0044-021X, Cummins, Carole ORCID: 0000-0001-5464-1944, Wheatley, Keith and Ives, Natalie J ORCID: 0000-0002-1664-7541
(2019) Sixteen-week versus standard eight-week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT. Health technology assessment (Winchester, England), 23 (26). 1 - 108.

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Abstract

<h4>Background</h4>The optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS).<h4>Objectives</h4>The primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs.<h4>Design</h4>Randomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis.<h4>Setting</h4>One hundred and twenty-five UK paediatric departments.<h4>Participants</h4>Two hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years).<h4>Interventions</h4>The control group (<i>n</i> = 118) received standard course (SC) prednisolone therapy: 60 mg/m<sup>2</sup>/day of prednisolone in weeks 1-4, 40 mg/m<sup>2</sup> of prednisolone on alternate days in weeks 5-8 and matching placebo on alternate days in weeks 9-18 (total 2240 mg/m<sup>2</sup>). The intervention group (<i>n</i> = 119) received extended course (EC) prednisolone therapy: 60 mg/m<sup>2</sup>/day of prednisolone in weeks 1-4; started at 60 mg/m<sup>2</sup> of prednisolone on alternate days in weeks 5-16, tapering by 10 mg/m<sup>2</sup> every 2 weeks (total 3150 mg/m<sup>2</sup>).<h4>Main outcome measures</h4>The primary outcome measure was time to first relapse [Albustix<sup>®</sup> (Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria]. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change [using Achenbach Child Behaviour Checklist (ACBC)]. A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months.<h4>Results</h4>There was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rank <i>p</i> = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%; <i>p</i> = 0.7), SDNS (44% vs. 42%; <i>p</i> = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%; <i>p</i> = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (<i>p</i> = 0.07). SAE rates were not significantly different (25% vs. 17%; <i>p</i> = 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit [0.0162 additional quality-adjusted life-years (QALYs)] and cost savings (£4369 vs. £2696).<h4>Limitations</h4>Study drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating.<h4>Conclusions</h4>This trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit.<h4>Future work</h4>Studies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted.<h4>Trial registration</h4>Current Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29.<h4>Funding</h4>This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in <i>Health Technology Assessment</i>; Vol. 23, No. 26. See the NIHR Journals Library website for further project information.

Item Type: Article
Uncontrolled Keywords: Humans, Nephrotic Syndrome, Recurrence, Prednisolone, Immunosuppressive Agents, Glucocorticoids, Drug Administration Schedule, Adolescent, Child, Child, Preschool, Infant, Cost-Benefit Analysis, Technology Assessment, Biomedical, Female, Male, Standard of Care
Depositing User: Symplectic Admin
Date Deposited: 04 Jun 2019 07:50
Last Modified: 14 May 2021 11:15
DOI: 10.3310/hta23260
URI: https://livrepository.liverpool.ac.uk/id/eprint/3044208