REducing STEroids in Relapsing Nephrotic syndrome: the RESTERN study— protocol of a national, double-blind, randomised, placebo-controlled, non-inferiority intervention study

Abstract

IntroductionOral corticosteroids are the first-line treatment for idiopathic childhood nephrotic syndrome. Most children experience several relapses, needing repeated courses of corticosteroid therapy. This exposes them to side effects and long-term complications. For most patients, long-term prognosis is for complete resolution of the disease over time and maintenance of normal kidney function. Therefore, it is vital to focus on minimising adverse events of the disease and its therapy. Unfortunately, no randomised controlled trials are available to determine the optimal corticosteroid treatment of an infrequent relapse of nephrotic syndrome. Recent studies show that treatment schedules for the first episode can safely be shortened to 2 months. The hypothesis of the REducing STEroids in Relapsing Nephrotic syndrome (RESTERN) study is that a 4-week reduction of alternate-day steroids after inducing remission is effective and safe, reduces steroid exposure by 35% on average and is therefore preferable.Methods and analysisThe RESTERN study is a nationwide, double-blind, randomised, placebo-controlled, non-inferiority intervention study. Children aged 1–18 years with a relapse of steroid-sensitive nephrotic syndrome are eligible for this study. Study subjects (n=144) will be randomly assigned to either current standard therapy in the Netherlands or a reduced prednisolone schedule. The primary outcome of the RESTERN study is the time to first relapse after the final prednisolone dose. The secondary outcomes are the number or relapses, progression to frequent relapsing or steroid dependent nephrotic syndrome and the cumulative dosage of prednisolone during the study period.Ethics and disseminationThis non-inferiority trial will be performed in accordance with the Declaration of Helsinki and has been approved by the medical ethical committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central Committee on Research Involving Human Subjects, CCMO). After completion of this study, results will be published in national and international peer-reviewed scientific journals. Papers will be published according to CCMO guidelines. The final report will be made available to trial participants.Trial registration numberNTR5670, EudraCT no 2016-002430-76.

Treatment Outcomes of Pediatric Nephrotic Syndrome Patients Treated in Ayder Comprehensive Specialized and Mekelle General Hospitals, Ethiopia

“…Patients developing FR/ SD NS require prolonged treatment that leads to toxicity, systemic infections, and other complications. [8][9][10] The common complications experienced with prolonged steroid treatment were cushingoid features, hypertension, hyperlipidemia, hyperglycemia, serious infections, growth retardation, stunted growth, osteopenia, and overall poor quality of life. 9,11 African children have an increased likelihood of developing focal segmental glomerulosclerosis.…”

“…15 Corticosteroids remained the first-line standard treatment for NS to achieve complete remission. 10 Despite the high rate of initial remission to corticosteroids therapy, relapses are common leading to increased morbidity and cost of treatment. 7 There is a wide inter-individual variation in the clinical course, treatment response, and treatment side effects among pediatrics, which makes it difficult to predict the treatment outcome.…”

Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome

“…Furthermore, a recently published abstract of the PREDNOS study indicated no clinical benefit associated with an extended steroid course for the initial presentation in UK children [ 6 ]. Currently, a few clinical trials are underway to further investigate the optimal dosing regimens for both the first manifestation ( https://clinicaltrials.gov/ct2/show/NCT02649413?recrs=abdf&cond=Nephrotic+Syndrome&age=0&draw=2&rank=13 ) as well as relapses of nephrotic syndrome [ 7 ].…”

“…Currently, a few clinical trials are underway to further investigate the optimal dosing regimens for both the first manifestation (https://clinicaltrials.gov/ct2/show/NCT02649413? recrs=abdf&cond=Nephrotic+Syndrome&age=0&draw= 2&rank=13) as well as relapses of nephrotic syndrome [7].…”

Optimizing the corticosteroid dose in steroid-sensitive nephrotic syndrome

“…The Italian PROPINE trial found no difference in time to next relapse when comparing corticosteroid courses that delivered the same cumulative dose over different durations [ 73 ], translating findings of prolonged corticosteroids for the initial episode into treatment for relapses, and thus questioning the practice of treating relapses with tapering consolidation corticosteroids. The on-going Dutch RESTERN trial will evaluate both cumulative dose (280 mg/m 2 versus 840 mg/m 2 ) and duration (2 versus 6 weeks) of the consolidation phase [ 74 ].…”