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

Abstract

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 (≤ 5or≥ 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.