#NephJC Chat
Tuesday Jan 25 2022 9 pm Eastern
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JAMA Pediatr 2021 Dec 20;e215189. doi: 10.1001/jamapediatrics.2021.5189. Online ahead of print.
Evaluation of Daily Low-Dose Prednisolone During Upper Respiratory Tract Infection to Prevent Relapse in Children With Relapsing Steroid-Sensitive Nephrotic Syndrome: The PREDNOS 2 Randomized Clinical Trial
Martin T Christian, Nicholas J A Webb, Samir Mehta, Rebecca L Woolley, Nafsika Afentou, Emma Frew, Elizabeth A Brettell, Adam R Khan, David V Milford, Detlef Bockenhauer, Moin A Saleem, Angela S Hall, Ania Koziell, Heather Maxwell, Shivaram Hegde, Hitesh Prajapati, Rodney D Gilbert, Caroline Jones, Karl McKeever, Wendy Cook, Natalie Ives
PMID: 34928294
AND
Pediatr Nephrol 2021 Oct;36(10):3143-3150. doi: 10.1007/s00467-021-05048-1. Epub 2021 Apr 16.
Low-dose versus conventional-dose prednisolone for nephrotic syndrome relapses: a randomized controlled non-inferiority trial
Seenam Sheikh, Kirtisudha Mishra, Manish Kumar
PMID: 33861375
Introduction
Nephrotic syndrome is the most common glomerular disease in children. It is characterized by the triad of proteinuria, hypoalbuminemia and edema (Noone et al, Lancet 2018). For over 60 years, corticosteroids have been the first line therapy, since most children have steroid sensitive nephrotic syndrome (SSNS). However, over 80% experience one or more relapses and around 50% are frequent relapsers (FRNS) and require multiple courses of steroids (Downie et al, Paediatric Int Child Health 2017). This puts them at high risk of short- and long-term complications of steroid therapy.
Research in SSNS is focused of identifying the causes of relapse and how to optimize the use of steroids to treat these episodes. Most relapses are triggered by intercurrent infections, with the most common being upper respiratory tract infections (URTI) (Gulati et al, CJASN 2011).
The KDIGO Glomerular diseases guideline 2021 made the following practice point for treating children aged 1 to 18 years presenting with a relapse:
Practice Point 4.3.2.1: The initial approach to relapse should include oral prednisone/prednisolone as a single daily dose of 60 mg/m2/d or 2 mg/kg/d (maximum 60 mg/d) until the child remits completely for ≥ 3 days.
Practice Point 4.3.2.2: After achieving complete remission, reduce oral prednisone/prednisolone to 40 mg/m2 or 1.5 mg/kg (maximum 50 mg) on alternate days for ≥ 4 weeks.
Recommendation 4.3.2.1: For children with frequently relapsing and steroid-dependent nephrotic syndrome who are currently taking alternate-day glucocorticoids or are off glucocorticoids, we recommend that daily glucocorticoids 0.5 mg/kg/d be given during episodes of upper respiratory tract and other infections for 5–7 days to reduce the risk of relapse (1C).
This week we will discuss two randomized controlled trials, which put these recommendations to the test:
The use of a 6-day course of low-dose daily prednisolone for the treatment of URTI-related relapse (URR). (Christian MT et al, JAMA Pediatr 2021, The PREDNOS 2 RCT).
Low dose vs standard dose prednisolone as treatment for nephrotic syndrome relapses (Sheikh et al, Pediatr Nephrol 2021).
PREDNOS 2
Relapses of SSNS have been long thought to be precipitated by viral upper respiratory tract infection (URTI) (Uwaezoke, Ital J Peds, 2015). Several previous small single center studies suggested giving low-dose daily prednisolone during an URTI to reduce the risk of relapse. A single center prospective study (n=36) reported that daily steroids at onset of URTI reduced total relapse episodes/patient at two years compared with alternate-day prednisone (Matoo et al, Nephron 2000). Another randomised double-blind placebo controlled crossover trial (n=48) reported that switching prednisolone from alternate-day to daily for 7 consecutive days at the same dose during the onset of a presumed viral URTI significantly reduced the risk of relapse in children with SSNS (Abeyagunawardena et al, Arch Dis Childhood 2008). An open-label, parallel group RCT (n=100) found that daily administration of maintenance doses of prednisolone, during intercurrent infections, significantly reduced relapse rates in children with FRNS (Gulati et al, CJASN 2011). Another double-blind placebo controlled crossover trial (n=48) reported that starting daily steroids in children (who were NOT on steroids for at least 3 months prior) prevented URTI related relapse (Abeyagunawardena et al, Pediatr Nephrol 2017). These studies were the basis of the above mentioned practice guideline (4.3.2.1). However, a Cochrane meta-analysis identified several sources of bias in these studies, including: small size, lack of blinding in several studies, and cross-over design (where the first treatment can influence response to the second treatment) (Hahn et al, CDSR, 2020). PREDNOS 2 was designed to answer this concern.
Studies of daily steroids with URTI to prevent relapse: VA by Archana Vajjala
Methods
Question
In children with SSNS, does daily low-dose corticosteroid given at the time of URTI prevent infection–related relapse?
Design
This multi-center, prospective, double-blind, placebo-controlled randomized controlled clinical trial was conducted from February 2013 to January 2020 at 122 centers in the United Kingdom. Data from the modified intention-to-treat population were analyzed from July 1, 2020, to December 31, 2020
Study population
Inclusion criteria:
Children 1 to 18 years of age with SSNS and 2 or more relapses in the preceding 12 months
Exclusion criteria:
Children with steroid-resistant nephrotic syndrome
Children receiving, or within 3 months of completing, a course of cyclophosphamide or rituximab
Children receiving daily prednisolone therapy
Children taking an alternate-day prednisolone dose greater than 15mg/m2
Intervention
Children were randomized in a 1:1 ratio
At the start of an upper respiratory tract infection:
Treatment group: received 6 days of prednisolone, 15mg/m2 daily
Placebo group: received matching placebo preparation (equivalent number of identical placebo tablets)
Children already taking alternate-day prednisolone rounded their daily dose using trial medication to the equivalent of 15mg/m2 daily or their alternate-day dose, whichever was greater. Children were followed for 12 months after receiving their intervention, with 3 monthly outpatient visits. Relapses were treated with standard therapy.
Definitions
URTI was defined as the presence of at least 2 of the following for at least 24 hours: sore throat, ear pain or discharge, runny nose, cough, hoarse voice, or temperature higher than 37° C
Relapse was defined as urine dipstick proteinuria (≥3+) for 3 consecutive days or the presence of generalized edema with proteinuria (3+)
URTI Related Relapse (URR) was defined as a relapse that occurred within 14 days of the development of a URTI
Outcomes
Primary outcome: the incidence of first upper respiratory tract infection–related relapse (URR).
Secondary outcomes
Overall rate of relapse (URRs and non-URTI related)
Changes in background immunosuppressive treatment
Cumulative dose of prednisolone during 12 months
Rates of serious adverse events
Incidence of corticosteroid adverse effects
Change in behavior measured by Achenbach Child Behavioral Checklist (ACBC)
Quality of life measured using Pediatric Quality of Life Inventory and the Child Health Utility Index–9 Dimension or EuroQoL 5-Dimension18 instruments (dependent on the child’s age)
Sample size calculation
Investigators estimated that half of URTI would cause a relapse, and then powered the trial to detect a 17.5% (ie, 35% proportional reduction) in URR rate (ie, from 50% to 32.5%), with 80% power and α = .05. This required 250 children. To account for a 15% attrition rate, the sample size was increased to 300 children (150 in each arm). During the trial, many children were not developing URTI, requiring the investigators to increase the anticipated trial size to 360 to maintain their power estimate.
Results
Of the 365 children randomized, 271 had an URTI, received study drug, and completed follow-up, resulting in the modified intension to treat population used for evaluating outcomes; prednisolone (n = 134) and placebo (n = 137).
3 patients in the treatment arm & 5 patients in the placebo arm had URTIs but withdrew early (no information given on URTI or URR)
1 patient in the placebo arm had a URTI (no information given on any URR)
Baseline characteristics
The baseline demographic characteristics for the modified intention-to-treat population are given in Table 1. The age at first nephrotic syndrome was about 4, while age at randomization was about 7.5 years and 64% were boys. At enrollment, about a quarter were off all immunosuppressants, while 25-30% were on steroids. About two-thirds were white and a fifth were South Asian.
Primary Outcome
A total of 56/131 children (42.7%) experienced a URR in the prednisolone arm and 58/131 (44.3%) in the placebo arm (adjusted risk difference, -0.02; 95% CI, -0.14 to 0.10; P = .70).
A post hoc subgroup analysis that assessed the primary outcome in those of South Asian ethnicity (risk ratio, 0.66; 95% CI, 0.40-1.10) vs other ethnicities and found no difference.
Secondary outcomes
There were no significant differences in these either
216 relapses (URTI and non–URTI related) in 91 children in the prednisolone arm vs 237 relapses in 98 children in the placebo arm (p=0.33)
Background treatment was escalated on at least 1 occasion in 58/130 children (44.6%) in the prednisolone arm vs 57/128 children (44.5%) in the placebo arm (p=0.96).
55/128 children (43.0%) in the prednisolone arm had at least 1 treatment reduction during the trial vs 62/129 children (48.1%) in the placebo arm (p =0 .42)
Median cumulative dose of prednisolone during 12 months was 2060mg in the prednisolone arm vs 1880mg in the placebo arm (p =0.72).
No significant differences were found between trial arms in:
Number of serious adverse events or specific corticosteroid adverse effects
Behavior scores measured using ACBC
Quality of life
Discussion
Unlike the 4 previous trials, and counter to the KDIGO guidelines, the PREDNOS 2 trial found that in children with relapsing SSNS, giving 6 days of daily low-dose prednisolone during an URTI does not reduce the risk of a relapse.
These findings clearly negate observations seen in previous trials, where a benefit of daily prednisolone therapy at the time of URTI was reported. Previous studies had multiple methodological limitations. A comparison of the populations for all 5 trials is given in Table 3.
Average age at recruitment was similar in previous trials and PREDNOS 2.
Overall frequency of relapses during the trial was similar, but the rate of infections was lower for PREDNOS 2.
While ethnicity wasn’t addressed in any of the previous studies, it is assumed that the samples taken were from local populations of homogeneous ethnicity. In this trial, children were recruited from diverse ethnic backgrounds, and differences in response according to ethnicity was nonsignificant.
Strengths
Double-blind, multicenter placebo-controlled trial
Larger size than all previous studies
Inclusivity: the only study to involve children receiving all types of background treatment
Systematic recording: the only trial to record corticosteroid adverse events (including effect on behavior)
Limitations
In contrast to previous studies, children weren’t examined at the time of their URTI. This may have led to incorrectly excluding children with URTI episodes not captured by definition. It is unlikely though that this led to a type 2 error. Had a type 2 error been made by failing to find a significant result that is present, an increased number of relapses would've been seen. However, the small increase in patients experiencing any relapses in the placebo arm was non-significant.
Conclusion
This RCT is the largest clinical trial of an investigational medication in children with nephrotic syndrome. PREDNOS 2 found no benefit of a short course of daily low-dose prednisolone at the time of a URTI. The large size of the trial makes its results more reliable and is therefore likely to change the Cochrane meta-analysis on this issue.
Further studies are needed to investigate the pathogenesis of viral infections and nephrotic syndrome.
Sheikh et al
Corticosteroids have been the mainstay of therapy for childhood SSNS for over 60 years. Chronic steroid use results in multiple side effects (Lee, JM et al, Acta Paediatr 2020). Recent well conducted RCT’s demonstrated that extended steroid therapy (6 months) compared with 2–3 months did not reduce the risk of relapse, the development of frequent relapses, or steroid dependence for the initial episode of nephrotic syndrome (Hahn et al, Cochrane Library, 2020)
There are no large RCTs looking at the use of low-dose steroids in SSNS relapse. Due to the lack of evidence, the KDIGO Glomerular diseases guideline 2021 recommend daily 60 mg/m2 or 2 mg/kg daily till remission for ≥ 3 days, then to reduce oral prednisone/prednisolone to 40 mg/m2 or 1.5 mg/kg (maximum 50 mg) on alternate days for at least 4 weeks. A recent small prospective pilot study randomized children with relapsed SNSS to receive 2, 1.5, or 1 mg/kg/day prednisolone and reported reduced cumulative steroid exposure with no difference in relapses during a short follow up period (Borovitz et al, Eur J Pediatr 2020). However the overall sample size in that trial was only 30, and the time to response was 7.2 ± 1.4, 10.2 ± 5.1, and 9 ± 3.3 days, with faster time to remission in the higher dose steroid. One patient in each of the lower dose groups also did not achieve remission; however the cumulative dose of steroids in the 1 mg/kg group was roughly half that found in the 2 mg/kg group. In the ongoing RESTERN trial, Children with SSNS (n=144) with relapse will be randomly assigned to 60 mg/m2 daily till remission then 40 mg/m2/alternate daily for 2 weeks and followed by placebo versus the standard 6 weeks regimen in a non-inferiority design.
VA by Archana Vajjala summarising the studies on dosing regimen of steroid for relapses in steroid sensitive nephrotic syndrome
Lowering the dose of steroids to treat relapses is desirable, but to study whether it is safe to do so requires a non-inferiority design: how much efficacy is one willing to give away for lower steroid exposure?
The trial from Sheikh et al is one such design which we will explore.
Methods
Question
Is the response of children with steroid sensitive nephrotic syndrome (SSNS) during a relapse the same when given low-dose prednisolone versus standard -dose prednisolone?
Design
This is a single-center, prospective, open-label, randomized controlled, non-inferiority trial, conducted from May 2018 to November 2019 in Delhi, India.
Study population
Inclusion criteria: Children aged 1–12 years of age with idiopathic SSNS, having a relapse
Exclusion criteria:
Children receiving or within 3 months of having received immunosuppressive medications like levamisole, cyclophosphamide, cyclosporine, or rituximab
Children with concurrent serious infections requiring hospitalization
Children with associated comorbidities
Allocation
Computer-generated block randomization sequence
Intervention (refer to fig. 1)
Standard care: oral prednisolone daily at 2 mg/kg/day (standard-dose group).
Low dose: oral prednisolone daily at 1 mg/kg/day (low-dose group)
Both groups were evaluated for remission (primary outcome), up to a maximum period of 2 weeks.
After achieving remission, prednisolone 1.5 mg/kg was administered on alternate days to both groups, as per Indian Society of Pediatric Nephrology (ISPN) guideline.
Inability to achieve remission by 2 weeks was considered “treatment failure” and retracted from the study
Therapy was switched to 2 mg/kg/day in low-dose group
Therapy continued at 2 mg/kg/day in standard-dose group
If remission was not achieved for a total period of 4 weeks, patients were considered “steroid resistant”, as per ISPN guidelines
All enrolled children were planned for a follow-up of 12 months and each relapse during follow-up was treated with a dose of prednisolone, as per their randomized group.
Outcomes
Primary outcome
Time to achieve remission following treatment of a relapse with low dose versus standard dose prednisolone. Remission was defined as a dipstick showing negative/trace for 3 consecutive days. Details about who performed this and how often this was done, or if the observer was blinded or not are not mentioned.
Secondary outcomes
Proportion of children achieving remission
Time to subsequent relapse
Total number of relapses, cumulative dose of steroids, and adverse effects of glucocorticoids follow-up over the subsequent 12 months
Statistical analysis
Sample size calculation: The authors estimated that the median time to remission would be 8 ± 2.5 days with standard-dose therapy. A non-inferiority margin of 2 days was then chosen (ie 2 days later remission with low dose would be considered non-inferior). For 90% power, and α-0.05, 60 patients were planned to be enrolled, allowing 10% loss to follow up.
Results
73 children presented with relapse and were assessed for eligibility for enrolment. 62 were eligible, out of which 60 consented, and 30 each were randomized in 2 groups: low-dose and standard-dose. One child in the low dose group and three in the standard dose group failed to achieve remission by 2 weeks so were retracted from the study. Twenty-nine (low dose) and 27 (standard dose) patients were analyzed for primary outcome as per-protocol analysis.
Baseline characteristics
Table 1 shows the demographic and clinical characteristics of randomized children with a SSNS according to the treatment group.
The study population was a typical cohort of childhood onset idiopathic nephrotic syndrome. The mean age of children in the study at recruitment was ~5 years with average duration of disease of 2 years. Nearly 60% of the children were boys. 52% of the children were infrequent relapsers, another 35% were frequent relapsers, 5% were steroid dependent and 8% had their first relapse. Time to first relapse was ~7 months with cumulative dose of steroids in the last 6 months being 71 mg/Kg, and in the last 12 months being ~132 mg/kg.
Primary Outcome
The time to remission was 9.0 ± 2.2 days in the low-dose group compared to 8.6 ± 2.2 days days in the standard-dose group. Thus the mean difference was 0.4 days. Since the upper limit of 95% CI was 1.6 days, less than the non-inferiority margin of 2 days, non-inferiority of low-dose prednisolone in relapse was established.
Secondary outcomes
The median time to the subsequent relapse was similar (86 days) in the low-dose group compared to that (150 days) in the standard-dose group, p = 0.39.
There was a similar proportion of children with subsequent relapses (80% with low dose vs 67% with standard dose), and a similar number of children diagnosed with frequent relapse/steroid-dependent forms (37 with low dose vs 17% with standard dose). (All P values NS)
The cumulative dose of steroids was similar in the low dose group as the standard dose (119 vs 145 mg/kg).
Figure 3 above also mentions 3 patients with ‘late treatment failure’ in the low dose group, though it is not mentioned what that means.
Discussion
The authors of this prospective, randomized controlled, open-labeled, non-inferiority trial, concluded that in children with SSNS, the time to achieve remission after treatment of a relapse with low-dose oral prednisolone was non-inferior to that after treatment with conventional dose. In addition, the proportion of children achieving remission by 2 weeks was similar in both groups.
The strength of the study is the use of randomized design to test the use of low dose prednisolone to induce remission in children with SSNS.
Some limitations
Open label design, and the outcome assessment was not blinded
Non-inferiority margin of 2 days is not a clinically relevant outcome; other outcomes that would be relevant might be: duration of remission/period until next relapse; proportion who develop steroid dependent or frequent relapsing pattern. These outcomes were not significantly worse in the low dose group, but the study was not powered for these secondary outcomes. Thus the study was powered for a less relevant outcome, and underpowered for the truly relevant outcome, which had trends to worse outcomes in the low dose group.
‘Late treatment failures’ were also seen in the low dose group, but are not clearly explained outside the figure alone
Despite the use of low dose steroids, the cumulative dose of steroids was not low enough to achieve significance, possibly as more patients did end up requiring steroids again subsequently.
Conclusion
Even though the authors of this RCT concluded that in children with SSNS, the time to achieve remission after treatment of a relapse with low-dose prednisolone is non-inferior to that after treatment with standard-dose prednisolone, this study was too small and had multiple limitations. Indeed, it is quite plausible that 1 mg/kg/day does achieve remission quickly, but the downside is that this may not be a lasting remission. We await further large, well conducted randomized controlled studies to answer the longer term safety outcomes definitively.
Summary prepared by Jana Sharara;
MS3, School of Medicine,
Lebanese American University, Byblos, Lebanon
Reviewed by Swasti Chaturvedi and Swapnil Hiremath