Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: phase III randomised controlled trial and economic evaluation.

OBJECTIVE: To determine whether extending initial prednisolone treatment from eight to 16 weeks in children with idiopathic steroid sensitive nephrotic syndrome improves the pattern of disease relapse. DESIGN: Double blind, parallel group, phase III randomised placebo controlled trial, including a cost effectiveness analysis. SETTING: 125 UK National Health Service district general hospitals and tertiary paediatric nephrology centres. PARTICIPANTS: 237 children aged 1-14 years with a first episode of steroid sensitive nephrotic syndrome. INTERVENTIONS: Children were randomised to receive an extended 16 week course of prednisolone (total dose 3150 mg/m2) or a standard eight week course of prednisolone (total dose 2240 mg/m2). The drug was supplied as 5 mg tablets alongside matching placebo so that participants in both groups received the same number of tablets at any time point in the study. A minimisation algorithm ensured balanced treatment allocation by ethnicity (South Asian, white, or other) and age (5 years or less, 6 years or more). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse over a minimum follow-up of 24 months. Secondary outcome measures were relapse rate, incidence of frequently relapsing nephrotic syndrome and steroid dependent nephrotic syndrome, use of alternative immunosuppressive treatment, rates of adverse events, behavioural change using the Achenbach child behaviour checklist, quality adjusted life years, and cost effectiveness from a healthcare perspective. Analysis was by intention to treat. RESULTS: No significant difference was found in time to first relapse (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17, log rank P=0.28) or in the incidence of frequently relapsing nephrotic syndrome (extended course 60/114 (53%) v standard course 55/109 (50%), P=0.75), steroid dependent nephrotic syndrome (48/114 (42%) v 48/109 (44%), P=0.77), or requirement for alternative immunosuppressive treatment (62/114 (54%) v 61/109 (56%), P=0.81). Total prednisolone dose after completion of the trial drug was 6674 mg for the extended course versus 5475 mg for the standard course (P=0.07). There were no statistically significant differences in serious adverse event rates (extended course 19/114 (17%) v standard course 27/109 (25%), P=0.13) or adverse event rates, with the exception of behaviour, which was poorer in the standard course group. Scores on the Achenbach child behaviour checklist did not, however, differ. Extended course treatment was associated with a mean increase in generic quality of life (0.0162 additional quality adjusted life years, 95% confidence interval -0.005 to 0.037) and cost savings (difference -£1673 ($2160; €1930), 95% confidence interval -£3455 to £109). CONCLUSIONS: Clinical outcomes did not improve when the initial course of prednisolone treatment was extended from eight to 16 weeks in UK children with steroid sensitive nephrotic syndrome. However, evidence was found of a short term health economic benefit through reduced resource use and increased quality of life. TRIAL REGISTRATION: ISRCTN16645249; EudraCT 2010-022489-29.

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

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.

Steroid-sensitive nephrotic syndrome (SSNS) is one of the most common childhood kidney diseases. The kidney filters leak protein into the urine, resulting in low levels of protein in the blood and generalised swelling. If untreated, this can lead to serious complications, including infection and blood clots. The disease responds well to prednisolone, a steroid drug; however, it is very common for disease to recur (called a relapse). Doctors are uncertain how long prednisolone should be given to treat children when they first present with nephrotic syndrome. In the UK, a 2-month course has traditionally been used. However, a number of research studies have suggested that giving prednisolone for ≥ 3 months may reduce the number of children who relapse and also the number who develop lots of relapses (called frequently relapsing nephrotic syndrome; FRNS). We recruited 237 children presenting with SSNS. Half were given an 8-week standard course of prednisolone and the other half a 16-week extended course (EC). We used placebo (dummy tablets) so that the participants and doctors did not know which treatment group they were in. Participants were followed for a minimum of 24 months and monitored for the development of relapses and prednisolone side effects, including behavioural problems. A cost analysis was performed. Giving EC prednisolone did not delay the development of disease relapse. There was also no difference in the number of children who developed FRNS or steroid-dependent nephrotic syndrome or who needed to be given other treatments. The rate of prednisolone side effects was the similar in the two treatment groups. EC treatment was, however, cheaper by £1673. Therefore, we conclude that there is no clinical benefit associated with the administration of EC prednisolone therapy in UK children presenting for the first time with SSNS. However, EC therapy was cheaper than the standard treatment.

Mapping the Paediatric Quality of Life Inventory (PedsQL™) Generic Core Scales onto the Child Health Utility Index-9 Dimension (CHU-9D) Score for Economic Evaluation in Children.

BACKGROUND: The Paediatric Quality of Life Inventory (PedsQL™) questionnaire is a widely used, generic instrument designed for measuring health-related quality of life (HRQoL); however, it is not preference-based and therefore not suitable for cost-utility analysis. The Child Health Utility Index-9 Dimension (CHU-9D), however, is a preference-based instrument that has been primarily developed to support cost-utility analysis. OBJECTIVE: This paper presents a method for estimating CHU-9D index scores from responses to the PedsQL™ using data from a randomised controlled trial of prednisolone therapy for treatment of childhood corticosteroid-sensitive nephrotic syndrome. METHODS: HRQoL data were collected from children at randomisation, week 16, and months 12, 18, 24, 36 and 48. Observations on children aged 5 years and older were pooled across all data collection timepoints and were then randomised into an estimation (n = 279) and validation (n = 284) sample. A number of models were developed using the estimation data before internal validation. The best model was chosen using multi-stage selection criteria. RESULTS: Most of the models developed accurately predicted the CHU-9D mean index score. The best performing model was a generalised linear model (mean absolute error = 0.0408; mean square error = 0.0035). The proportion of index scores deviating from the observed scores by <  0.03 was 53%. CONCLUSIONS: The mapping algorithm provides an empirical tool for estimating CHU-9D index scores and for conducting cost-utility analyses within clinical studies that have only collected PedsQL™ data. It is valid for children aged 5 years or older. Caution should be exercised when using this with children younger than 5 years, older adolescents (>  13 years) or patient groups with particularly poor quality of life. ISRCTN REGISTRY NO: 16645249.