PMID- 31156083 OWN - NLM STAT- MEDLINE DCOM- 20200922 LR - 20210109 IS - 2046-4924 (Electronic) IS - 1366-5278 (Print) IS - 1366-5278 (Linking) VI - 23 IP - 26 DP - 2019 May TI - Sixteen-week versus standard eight-week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT. PG - 1-108 LID - 10.3310/hta23260 [doi] AB - 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 (/= 6 years). INTERVENTIONS: The control group (n = 118) received standard course (SC) prednisolone therapy: 60 mg/m(2)/day of prednisolone in weeks 1-4, 40 mg/m(2) of prednisolone on alternate days in weeks 5-8 and matching placebo on alternate days in weeks 9-18 (total 2240 mg/m(2)). The intervention group (n = 119) received extended course (EC) prednisolone therapy: 60 mg/m(2)/day of prednisolone in weeks 1-4; started at 60 mg/m(2) of prednisolone on alternate days in weeks 5-16, tapering by 10 mg/m(2) every 2 weeks (total 3150 mg/m(2)). MAIN OUTCOME MEASURES: The primary outcome measure was time to first relapse [Albustix((R)) (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 ( pound4369 vs. pound2696). 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. FAU - Webb, Nicholas Ja AU - Webb NJ AUID- ORCID: 0000-0001-8572-5446 AD - Department of Paediatric Nephrology, University of Manchester, Manchester Academic Health Science Centre, Royal Manchester Children's Hospital, Manchester, UK. FAU - Woolley, Rebecca L AU - Woolley RL AUID- ORCID: 0000-0001-5119-1431 AD - Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK. FAU - Lambe, Tosin AU - Lambe T AUID- ORCID: 0000-0002-6229-2454 AD - Health Economics Unit, University of Birmingham, Birmingham, UK. FAU - Frew, Emma AU - Frew E AUID- ORCID: 0000-0002-5462-1158 AD - Health Economics Unit, University of Birmingham, Birmingham, UK. FAU - Brettell, Elizabeth A AU - Brettell EA AUID- ORCID: 0000-0002-0669-3085 AD - Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK. FAU - Barsoum, Emma N AU - Barsoum EN AUID- ORCID: 0000-0003-4386-3917 AD - Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK. FAU - Trompeter, Richard S AU - Trompeter RS AUID- ORCID: 0000-0003-0044-021X AD - Centre for Nephrology, University College London, UK. FAU - Cummins, Carole AU - Cummins C AUID- ORCID: 0000-0001-5464-1944 AD - Institute of Applied Health Research, University of Birmingham, Birmingham, UK. FAU - Wheatley, Keith AU - Wheatley K AD - Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK. FAU - Ives, Natalie J AU - Ives NJ AUID- ORCID: 0000-0002-1664-7541 AD - Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK. LA - eng SI - ISRCTN/ISRCTN16645249 SI - EudraCT/2010-022489-29 GR - 08/53/31/DH_/Department of Health/United Kingdom PT - Clinical Trial PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Health Technol Assess JT - Health technology assessment (Winchester, England) JID - 9706284 RN - 0 (Glucocorticoids) RN - 0 (Immunosuppressive Agents) RN - 9PHQ9Y1OLM (Prednisolone) SB - IM MH - Adolescent MH - Child MH - Child, Preschool MH - Cost-Benefit Analysis MH - *Drug Administration Schedule MH - Female MH - Glucocorticoids/*therapeutic use MH - Humans MH - Immunosuppressive Agents/therapeutic use MH - Infant MH - Male MH - Nephrotic Syndrome/*drug therapy MH - Prednisolone/*therapeutic use MH - *Recurrence MH - Standard of Care MH - Technology Assessment, Biomedical PMC - PMC6571545 OAB - 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 pound1673. 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. OABL- eng OTO - NOTNLM OT - ADVERSE REACTIONS OT - CHILD OT - COST-BENEFIT ANALYSIS OT - DRUG-RELATED ADVERSE EFFECTS OT - NEPHROTIC SYNDROME OT - PLACEBO OT - PREDNISOLONE OT - RANDOMISED CONTROLLED TRIAL OT - RELAPSE COIS- 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. EDAT- 2019/06/04 06:00 MHDA- 2020/09/23 06:00 PMCR- 2019/06/17 CRDT- 2019/06/04 06:00 PHST- 2019/06/04 06:00 [entrez] PHST- 2019/06/04 06:00 [pubmed] PHST- 2020/09/23 06:00 [medline] PHST- 2019/06/17 00:00 [pmc-release] AID - 10.3310/hta23260 [doi] PST - ppublish SO - Health Technol Assess. 2019 May;23(26):1-108. doi: 10.3310/hta23260.