Background:

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).

Objectives:

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.

Design:

Randomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis.

Setting:

One hundred and twenty-five UK paediatric departments.

Participants:

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).

Interventions:

The control group (n = 118) received standard course (SC) prednisolone therapy: 60 mg/m²/day of prednisolone in weeks 1–4, 40 mg/m² of prednisolone on alternate days in weeks 5–8 and matching placebo on alternate days in weeks 9–18 (total 2240 mg/m²). The intervention group (n = 119) received extended course (EC) prednisolone therapy: 60 mg/m²/day of prednisolone in weeks 1–4; started at 60 mg/m² of prednisolone on alternate days in weeks 5–16, tapering by 10 mg/m² every 2 weeks (total 3150 mg/m²).

Main outcome measures:

The primary outcome measure was time to first relapse [Albustix^® (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.

Results:

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 p = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%; p = 0.7), SDNS (44% vs. 42%; p = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%; p = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (p = 0.07). SAE rates were not significantly different (25% vs. 17%; p = 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).

Limitations:

Study drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating.

Conclusions:

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.

Future work:

Studies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted.

Trial registration:

Current Controlled Trials ISRCTN16645249 and EudraCT 2010-022489-29.

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. 23, No. 26. See the NIHR Journals Library website for further project information.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 08/53/31. The contractual start date was in May 2011. The draft report began editorial review in September 2017 and was accepted for publication in February 2018. 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.

Declared competing interests of authors

Nicholas JA Webb has served on advisory boards within the past 5 years for AbbVie Inc. (North Chicago, IL, USA), Alexion Pharmaceuticals (New Haven, CT, USA), AMAG Pharmaceuticals Inc. (Waltham, MA, USA), Astellas Pharma Inc. (Tokyo, Japan), Raptor Pharmaceuticals (Novato, CA, USA), Takeda Pharmaceutical Company (Osaka, Japan) and UCB (Union Chimique Belge) (Brussels, Belgium). These have related to the design and conduct of early-phase trials in childhood kidney disease. None has been related to the treatment of corticosteroid-sensitive nephrotic syndrome. Since August 2018, Nicholas JA Webb has been Translational Medicine Discovery Director, Renal and Transplantation, at Novartis Institutes for BioMedical Research. Carole Cummins has received grants from Kidney Research UK and Kids Kidney Research.