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org clinical trial


& 2014 International Society of Nephrology

OPEN

A multicenter randomized trial indicates initial


prednisolone treatment for childhood nephrotic
syndrome for two months is not inferior to
six-month treatment
Norishige Yoshikawa1, Koichi Nakanishi1, Mayumi Sako2, Mari S. Oba3, Rintaro Mori4, Erika Ota4,
Kenji Ishikura5, Hiroshi Hataya5, Masataka Honda5, Shuichi Ito6, Yuko Shima1, Hiroshi Kaito7,
Kandai Nozu7, Hidefumi Nakamura2, Takashi Igarashi8, Yasuo Ohashi9 and Kazumoto Iijima7; for the
Japanese Study Group of Kidney Disease in Children10
1
Department of Pediatrics, Wakayama Medical University, Wakayama City, Japan; 2Division for Clinical Trials, Clinical Research Center,
National Center for Child Health and Development, Tokyo, Japan; 3Department of Biostatistics and Epidemiology, Graduate School
of Medicine, Yokohama City University, Yokohama, Japan; 4Department of Health Policy, National Center for Child Health and
Development, Tokyo, Japan; 5Department of Nephrology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan; 6Department
of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan; 7Department of Pediatrics,
Kobe University Graduate School of Medicine, Kobe, Japan; 8National Center for Child Health and Development, Tokyo, Japan and
9
Department of Biostatistics, School of Public Health, The University of Tokyo, Tokyo, Japan

In this multicenter, open-label, randomized controlled trial, to 6 months of initial therapy in terms of time to onset of
we determined whether 2-month prednisolone therapy for frequently relapsing nephrotic syndrome.
steroid-sensitive nephrotic syndrome was inferior or not to Kidney International advance online publication, 23 July 2014;
6-month therapy despite significantly less steroid exposure. doi:10.1038/ki.2014.260
The primary end point was time from start of initial treatment KEYWORDS: initial treatment; nephrotic syndrome; pediatric nephrology;
to start of frequently relapsing nephrotic syndrome. The pre- randomized controlled trial; steroid
specified non-inferiority margin was a hazard ratio of 1.3 with
one-sided significance of 5%. We randomly assigned 255
children with an initial episode of steroid-sensitive nephrotic
syndrome to either 2 - or 6-month treatment of which 246 Idiopathic nephrotic syndrome (NS) is a disorder affecting
were eligible for final analysis. The total prednisolone the kidneys that is mainly characterized by high excretion of
exposure counted both initial and relapse prednisolone protein in the urine. Pediatric idiopathic NS is understood to
treatment administered over 24 months. Median follow-up in be the most common cause of primary glomerular diseases,
months was 36.7 in the 2-month and 38.2 in the 6-month and it frequently occurs in infants aged 2–6 years. Most
treatment group. Time to frequent relaps was similar in both patients are presumed to have minor glomerular abnor-
groups; however, the median was reached only in the 6- mality. Cellular immunologic abnormalities are believed to
month group (799 days). The hazard ratio was 0.86 (90% contribute to the condition, although its pathology remains
confidence interval, 0.64–1.16) and met the non-inferior unknown. In Europe and the United States, two in 100,000
margin. Time to first relapse was also similar in both groups: children will develop idiopathic NS in a single year.1 An
median day 242 (2-month) and 243 (6-month). Frequency 8-week corticosteroid regimen is the standard initial treat-
and severity of adverse events were similar in both groups. ment for children with idiopathic NS, as outlined by
Most adverse events were transient and occurred during the International Study of Kidney Disease in Children
initial or relapse therapy. Thus, 2 months of initial (ISKDC).2,3 Although corticosteroids induce the remission
prednisolone therapy for steroid-sensitive nephrotic of proteinuria in more than 80% of children with idiopathic
syndrome, despite less prednisolone exposure, is not inferior NS, B60% undergo proteinuria relapse. Previous research
has shown that a high number of children undergo frequent
Correspondence: Norishige Yoshikawa, Department of Pediatrics, Wakayama relapse, and corticosteroid toxicities occur after repeated
Medical University, 811-1 Kimiidera, Wakayama City 641-8510, Japan. therapy.2,3 Although some controlled studies4–7 and a meta-
E-mail: nori@wakayama-med.ac.jp analysis8 show that long-term corticosteroid treatment up to
10
See appendix. 7 months maximum leads to a longer sustained remission of
Received 4 February 2014; revised 29 May 2014; accepted 5 June 2014 NS than ISKDC-recommended administration, the optimum

Kidney International 1
clinical trial N Yoshikawa et al.: RCT for initial prednisolone in childhood NS

dose and duration of initial therapy are still unknown. (comprising 45 FRNS [definition 1, 23; definition 2, 22],
A Cochrane review concluded that a well-designed and and 13 requiring immunosuppressant administration).
adequately powered randomized controlled trial is required Twenty-one patients required immunosuppressants owing
to establish the optimum dose and duration of treatment.8 to steroid-dependent or steroid-resistant relapse. Times to
The purpose of this study is to investigate whether 2 months FRNS were similar in both groups: however, the median
of initial prednisolone therapy (ISKDC regimen) is not duration of time to FRNS was reached only in the 6-month
inferior to 6 months of initial therapy with an increasing group (at 799 days). The hazard ratio (HR) was 0.86 (90%
cumulative dose, and to compare adverse events between confidence interval (CI), 0.64–1.16; Figure 2), and noninfer-
treatment regimens. iority of the 2-month group was confirmed significantly, with
an HR margin of 1.3 (P ¼ 0.01). Post-hoc analyses showed
RESULTS that age groups did not affect the median duration of time to
Patient population FRNS. The HRs (95% CI) were 0.92 (0.59–1.45), 0.86
The study was conducted from September 6, 2007 until (0.41–1.84), and 0.74 (0.31–1.77) for the age groups 1–5 years,
February 8, 2013. Figure 1 shows the trial profile. We assessed 6–10 years, and 11–15 years, respectively.
255 patients from 90 hospitals (61 general, 7 children’s, and
22 university hospitals) for eligibility. We randomly assigned Secondary end points
128 patients to the 2-month prednisolone group and 127 Times to first relapse were similar in both groups: the median
patients to the 6-month prednisolone group. We excluded was 242 days and 243 days in the 2-month and 6-month
nine patients from the analysis: six did not receive trial treatment groups, respectively (HR ¼ 0.97; 95% CI,
medication because of either early relapse after remission 0.72–1.31; P ¼ 0.86; Figure 3). The number of relapses per
during the initial 4-week prednisolone treatment, or with- person-year during the trial intervention period was 1.25
drawn consent, and three were excluded owing to a lack of times in the 2-month group and 1.33 times in the 6-month
participant data. Thus, we analyzed data for 246 patients. group, and the ratio was 0.94 (95% CI, 0.71–1.22; P ¼ 0.65,
Median follow-up was 36.7 months in the 2-month group Table 2). The median cumulative dose of prednisolone
(interquartile range 27.8–46.4 months) and 38.2 months in during the 2-year trial period in the 2-month group was
the 6-month group (interquartile range 28.6–48.5 months). also significantly lower than in the 6-month group (4621.9
There was no difference in characteristics between the two [interquartile range ¼ 2191.3–7472.5] vs. 6484.8 [inter-
groups (Table 1). quartile range ¼ 3701.0–9577.9], Po0.001).

Primary end point Adverse events


The primary end point was defined as the duration from Frequency and severity of adverse events were similar in both
start of initial treatment to diagnosis of frequently relapsing groups (Table 3). Most adverse events were transient and
nephrotic syndrome (FRNS), or ‘time to FRNS’. By the end occurred during initial therapy or relapse therapy. In our
of the 24-month intervention period, we observed 54 events study, steroid dependency did not greatly affect the occur-
in the 2-month group (comprising 46 FRNS [definition 1, 28; rence of adverse events. Two patients in the 2-month group
definition 2, 18], and 8 requiring immunosuppressant had severe adverse events requiring hospitalization. One
administration) and 58 events in the 6-month group patient discontinued because of acute kidney failure during

255 Patients assessed for eligibility

255 Patients randomly assigned

128 Patients assigned to 127 Patients assigned to


2-month prednisolone 6-month prednisolone

4 Were excluded: 5 Were excluded:


3 Early relapse after remission 2 Early relapse after remission
during the initial 4-week during the initial 4-week
prednisolone prednisolone
1 No follow-up data available 1 Withdrew consent before
allocated trial medication
2 No follow-up data available

124 Patients analyzed 122 Patients analyzed

Figure 1 | Trial profile.

2 Kidney International
N Yoshikawa et al.: RCT for initial prednisolone in childhood NS clinical trial

Table 1 | Baseline characteristics


2-Month prednisolone (n ¼ 124) 6-Month prednisolone (n ¼ 122) P-value
Male, n (%) 89 (71.8) 87 (71.3) 0.94
Age, mean (s.d.), years 6.7 (4.1) 6.3 (4.1) 0.42

Age group, years


1–5, n (%) 67 (54.0) 66 (54.1) 0.99
6–10, n (%) 33 (26.6) 33 (27.1)
11–15, n (%) 24 (19.4) 23 (18.9)

Blood pressure, mean (s.d.), mm Hg


Systolic 104.4 (10.7) 106.4 (12.0) 0.16
Diastolic 62.4 (10.0) 62.5 (11.3) 0.98
Serum albumin, mean (s.d.), g/l 1.4 (0.5) 1.4 (0.5) 0.90

Hospital, n (%)
General 47 (65.3) 46 (64.8) 1.00
Children’s 7 (9.7) 7 (9.9)
University 18 (25.0) 18 (25.4)

Quarterly distribution of disease onset, n (%)


January–March 23 (18.7) 24 (19.7) 0.99
April–June 36 (29.3) 34 (27.9)
July–September 30 (24.4) 31 (25.4)
October–December 34 (27.6) 33 (27.0)
Duration from the first episode to remission, mean (s.d.), days 9.7 (3.1) 10.0 (3.1) 0.45
Abbreviation: s.d., standard deviation.

HR for FRNS: 0.86 (90% Cl, 0.64–1.16) HR for times to first relapse: 0.97
1.0 1.0
Non-inferiority with HR margin 1.3 (95% Cl, 0.72–1.31; P =0.86)
Non- frequent relapse rate

0.9 0.9
of 2-month group: P = 0.01
0.8 0.8
Relapse-free rate

0.7 0.7
0.6 0.6
0.5 0.5
0.4 0.4
0.3 0.3
0.2 2-Month prednisolone
0.2 2-Month prednisolone
0.1 6-Month prednisolone
0.1 6-Month prednisolone
0.0 0.0
0 12 24 36 48
0 12 24 36 48
Time (month)
Number at risk Time (month)
Number at risk
2-Month group 124 86 64 34 11
2-Month group 124 48 40 19 4
6-Month group 122 82 55 29 14
6-Month group 122 50 34 15 6
Figure 2 | Kaplan–Meier estimates of time to frequently relapsing
nephrotic syndrome (FRNS). HR, hazard ratio. Figure 3 | Kaplan–Meier estimates of time to first relapse.
HR, hazard ratio.

relapse (month 10) and recovered in 22 days. Another patient of prednisolone. Symptoms disappeared on the same day of
had pneumonia with influenza infection on the last date onset without further treatment.
of the 2-month prednisolone treatment and recovered in
10 days. Height standard deviation scores show a significant DISCUSSION
decrease in growth at 2 months of follow-up compared with Extension of initial steroid treatment for more than 3 months
baseline (Po0.003). In both groups, this was restored within to decrease the risk of relapse in children with steroid-
9 months after initial treatment commenced. Notably, one sensitive (SS) NS has been widely described in previous
patient in the 6-month group was diagnosed with possible studies.4–10 However, 80–90% of children diagnosed with
adrenal insufficiency owing to steroid withdrawal according SSNS who are given new corticosteroid treatments continue
to clinical symptoms (mild headache and mild nausea) when to relapse, and B50% relapse frequently.11 Therefore, initial
the patient switched to trial medication after the initial dose approaches to SSNS therapy are likely to be substantially

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clinical trial N Yoshikawa et al.: RCT for initial prednisolone in childhood NS

Table 2 | Number of relapses


Total number Duration of observation The number of relapses Ratio of the number
of relapses (person-year) (per person-year) of relapses (CI) P-value
2-Month prednisolone 301 240.93 1.25 0.94 0.65
6-Month prednisolone 309 232.62 1.33 (0.71–1.22)
Abbreviation: CI, confidence interval.

Table 3 | Adverse events during the 24-month trial still required to determine the most effective duration and
intervention perioda dosage regimen for initial SSNS.
2-Month 6-Month A key strength of our trial is its unique design. This is a
prednisolone prednisolone multicenter, randomized, controlled trial for noninferiority
Event n ¼ 124 n ¼ 122 P-value that compares the efficacy of the 2-month ISKDC regimen
Hypertension b
15 9 0.24 with a 6-month, long-term prednisolone regimen. The most
important clinical objective of initial treatment of SSNS is to
Cushingoid appearance
prevent frequent relapses. Consequently, the primary end
Cushing (moon face)b 54 61 0.46
Central obesityb 20 34 0.052 point was set to time to FRNS rather than initial relapses.
Striae 1 0 1.00 Our data from several analyses consistently support
Adrenal insufficiency 0 1 1.00 noninferiority of the ISKDC regimen. In the current trial, a
Ophthalmological abnormalities
HR threshold of 1.3 for noninferiority of the primary end
Glaucomab 19 13 0.31 point is slightly high given the feasible study size. However,
Cataract 0 0 the posterior probability that a HR would be smaller than
1.1 and 1.2 (HRs that are commonly used as an upper
Severe infections
Pneumoniac 1 0 1.00
equivalence margin) was 91 and 97%, respectively.
Peptic ulcer 1 0 1.00 In our trial, noninferiority was found in FRNS (primary
Acute kidney failurec 1 0 1.00 end point) and first relapse (secondary end point) between
Hyperglycemia 2 3 0.64 the ISKDC and 6-month regimens. This means that many
Increased laboratory data patients relapse even while taking tapering-dose prednisolone
ASTb 14 11 0.58 (Figure 3). Previous studies vary in their observation of
ALTb 26 16 0.14 (frequent) relapses from either the start or end of initial
Amylase 3 0 1.00 therapy.8,13 However, if analyses are performed from the end
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase.
a of initial therapy, relapses during tapering-dose prednisolone
Data are expressed as the number of events.
b
Multiple reports were recorded for these adverse events. cannot be counted, possibly resulting in an inadequate
c
Severe adverse events requiring hospitalization. interpretation. Therefore, we selected observations primarily
from the start of initial therapy. In our study design, steroid-
dependent NS was predicted to occur more frequently
because of its definition in the 6-month regimen. This is
different.12 Our results demonstrate that extending initial one reason why we selected FRNS as a primary end point,
steroid treatment, and even increasing the total dose of and not steroid-dependent NS. In fact, time to steroid-
prednisolone (2240 vs. 3885 mg/m2), does not improve dependent NS was significantly higher in the ISKDC regimen
clinical outcomes (time to FRNS, time to first relapse, the group (data not shown).
number of relapses, total prednisolone dose, and adverse No significant difference in adverse events was observed
events) for pediatric NS. Our results add to the Cochrane between the two regimens in our large-scale trial, which is a
review by Hodgson et al.8 by comparing treatment regimens similar finding to previous small-scale trials.4–7 Most adverse
of 2 vs. 6 months. events were transient and occurred during initial or relapse
Our findings build on a 2013 study from the Netherlands. therapy. However, because the ISKDC regimen is generally
This well-designed, randomized, double-blind, placebo-con- less likely to cause adverse events owing to the lower dosage
trolled trial of children with NS clearly showed no and the shorter duration, its use can be recommended.
improvement in clinical outcomes when the initial predni- A limitation of our trial is the open-label design, which
solone treatment was extended from 3 to 6 months without may have introduced preconception bias. However, as our
an increasing cumulative dose.13 However, despite the results trial design is a noninferiority trial with regular visits, and
of this trial, the most effective duration and dosage of relapses are measured objectively, we cannot assume positive
prednisolone treatment for an initial episode of SSNS is still placebo effects. Therefore, the open-label design of this study
under debate.14 Although our study has demonstrated that may have limited impact on preconception bias. Moreover,
increasing the total dose in 2-month or 6-month regimens the results of this trial may partially be due to the relatively
does not improve clinical outcomes, further investigation is high rate of relapse compared with other studies.5 The high

4 Kidney International
N Yoshikawa et al.: RCT for initial prednisolone in childhood NS clinical trial

rate of relapse may be owing to our definition of relapse and the Declaration of Istanbul, and adhered to the International
(proteinuria 2 þ or higher). It still remains unknown Conference on Harmonisation Guidelines on Good Clinical
whether long prednisolone therapy consisting of a dose of Practice.
60 mg/m2 per day for 6 weeks, followed by alternate-day
doses of 40 mg/m2 per 2 days for 6 weeks, is more effective Randomization
against time to FRNS compared with the ISKDC regimen Patients were randomly assigned to either the 2-month or 6-month
for treating idiopathic NS. In our study, only one patient group in a 1:1 ratio at the Japan Clinical Research Support Unit. We
withdrew consent. A low rate of consent withdrawal is applied a minimization method using a computer-generated
common in Japan.15,16 Cultural differences between countries sequence (SAS PROC PLAN) with age (1–10 years or 11–15 years),
sex, and institution as adjustment (stratification) factors. Patients,
may account for variations in rates of consent withdrawal.
patients’ guardians, treating physicians, and individuals assessing
In our study, steroid sensitivity was confirmed by day 21 outcomes and analyzing data were not blinded to the patients’
in order to ensure time for eligibility screening. Generally, treatment assignments. Apart from the trial statistician and the
remission after 3 weeks is uncommon.17 Therefore, as the data-monitoring committee, all treating physicians and other
effect of early confirmation of steroid sensitivity was slight, investigators remained blinded to the trial results until follow-up
we decided to confirm steroid sensitivity by day 21. was completed.
We conducted a meta-analysis to address the differences
between corticosteroid regimens in children with an initial Procedures
episode of SSNS. We searched randomized controlled trials The first patient was randomized in September 2007, and the last
that compared durations of steroid therapy in children and patient in January 2011. Follow-up started at diagnosis and was
reported the number of FRNS cases within 2 years (see the truncated when the last enrolled patients finished the 24-month
Supplementary Information online for a detailed search intervention.
strategy). Meta-analysis of our study and five studies6,13,18,19 All patients diagnosed with a first episode of idiopathic NS
showed a risk ratio (long vs short) of 0.99 (95% CI, started initial therapy of 60 mg/m2 oral prednisolone in three
0.68–1.44, see Supplementary Figure 2A online), whereas divided doses (maximum of 80 mg/day) daily for 4 weeks. Patients
underwent a screening examination and were registered after their
meta-analysis of our study and the published studies only
eligibility, including remission, was verified. Participants switched to
showed an risk ratio of 1.15 (95% CI: 0.95–1.40, Supple- trial medication after initial doses of prednisolone were given
mentary Figure 2B online). This result might indicate that (Figure 4). If participants relapsed after remission during the initial
long-term treatment is not superior but almost equivalent to 4-week prednisolone treatment, they were excluded.
ISKDC-standard therapy. Trial medication consisted of initial treatment regimens and
In conclusion, our study shows that extending initial relapse treatment, and was completed within a total of 24 months in
prednisolone treatment from 2 to 6 months with an increas- both groups (Figures 4 and 5). The duration of long-term
ing dose does not improve clinical outcomes for pediatric NS. prednisolone treatment was set to 6 months, which is consistent
The original ISKDC regimen is not inferior to 6 months of with recommendations from a non-Japanese randomized controlled
initial therapy with an increasing cumulative dose. We assert trial.8 The cumulative dose of initial treatment was 2240 mg/m2
that the ISKDC regimen is recommended as an initial (2-month group) and 3885 mg/m2 (6-month group). Participants
treatment for pediatric idiopathic NS.
2-Month prednisolone
Cumulative dose: 2240 mg
MATERIALS AND METHODS
Study design and patients
We conducted a multicenter, randomized, noninferiority, open-label
trial at 90 hospitals in Japan and compared prednisolone treatment
of 2 months (ISKDC regimen) with 6 months for children with
a first episode of idiopathic NS. We diagnosed idiopathic NS and Dose 60D 40AD
(Max.) (80) (50)
remission according to the ISKDC.1 NS was defined as a urinary Week 1–4 5–8
protein–creatinine ratio X1.8 and albumin levels p25 g/l in serum.
Remission was defined as a negative dipstick analysis for 3 6-Month prednisolone
consecutive days. Patients aged 1–15 years with a first episode of Cumulative dose: 3885 mg
idiopathic NS were eligible if they had remission within 3 weeks of
prednisolone administration. Patients were ineligible if they had
secondary NS, renal insufficiency defined as creatinine clearance of
p60 ml/min per 1.73 m2, active infections, poorly controlled
hypertension, severe liver dysfunction, pregnancy, or a history of
immunosuppressant administration. Dose 60D 60AD 45AD 30AD 15AD 7–5AD
Before enrollment, patients’ guardians provided written in- (Max.) (80) (80) (60) (40) (20) (10)
formed consent, and informed assent was obtained from older Week 1–4 5–8 9 – 12 13 – 16 17 – 20 21 – 24
children. This study was approved by the institutional review boards Figure 4 | Initial treatment regimens. Upper doses are in mg/m2
of participating hospitals, complied with the Declaration of Helsinki per day. Maximum doses are in mg/day. D, daily; AD, alternate days.

Kidney International 5
clinical trial N Yoshikawa et al.: RCT for initial prednisolone in childhood NS

Basic regimen for relapse in secondary end points were time to first relapse, the number of
2-month group and relapse at no relapses per person-year, total prednisolone dose, and adverse events.
prednisolone in 6-month group
Statistical analyses
The primary objective of this trial was to confirm noninferiority of
initial therapy with 2-month treatment compared with 6-month
treatment, with respect to time to FRNS. The noninferiority margin
of HR for the 2-month to 6-month group was predefined to 1.3, and
Dose 60 60 30 15
Duration
the significance level was set to 5% (one-sided). The former
D AD AD AD
(Week) (a) (2) (2) (2) was determined based on surveys conducted among practicing
pediatric nephrologists and other specialists before the protocol was
Figure 5 | Treatment regimens for relapse. aUntil urinary protein is developed.
negative on 3 consecutive days using a urine dipstick test. Upper
On the basis of results from a previous study,20 we assumed an
doses are in mg/m2/day. A maximum dose of each is the same as
initial treatments in Figure 4. AD, alternate days; D, daily. event rate of 15 and 19% at 1 year in the 2- and 6-month groups,
respectively. With a sample size of 125 patients in each treatment
group, an HR test with a one-sided 5% significance level would have
70% power to confirm noninferiority. Accrual and follow-up times
who relapsed during the 24-month trial medication period received were specified to be 3 and 2 years, respectively.
relapse treatment regimens (Figure 5). Relapse treatment was the As the previous study20 was conducted more than 10 years
same in both groups. However, relapse treatment given during the earlier, it is possible that the current event rate of our study is lower
6-month initial treatment was adjusted according to the initial than the previous study. We scheduled an interim analysis to take
treatment regimen in the 6-month group. place just before the accrual completion date, which was performed
Participant characteristics (age, sex, physical characteristics, in October 2010. A statistical test regarding the primary end point
blood, and urine test results) were recorded at baseline. Clinical was not performed. The number of events observed matched that of
assessment and urine tests (urinalysis, qualitative and quantitative the assumption, and the study plan was not changed.
proteinuria, quantitative creatinine) were performed at 1, 2, 4, and 6 Statistical analyses followed the protocol and the intention-
months after enrollment and every 3 months thereafter, and also on to-treat principle. The Cox proportional hazard model was used
diagnosis of relapse. Blood analysis (complete blood cell count, to test noninferiority and estimate the HR with a 90% CI of the
blood chemistry) was performed at 1, 2, 6, and 12 months after primary end point. The Kaplan–Meier method was used to
enrollment, at the end of treatment, and at diagnosis of relapse only. summarize time to FRNS. These methods and the log-rank test
Adverse events were recorded throughout the trial period and were used to analyze time to first relapse. The number of relapses
assessed using Common Terminology Criteria for Adverse Events per person-year was calculated as the total number of relapses
v3.0. Within 4 weeks of starting initial treatment, participants were divided by the total observed person-years in each treatment group
screened for glaucoma by an ophthalmologist. Details about (Table 2). A permutation test was used to compare the number of
monitoring adverse events are described in the Supplementary relapses per person-year between groups. We compared the
Information online. Briefly, name of diagnosis, severity, seriousness, prednisolone total dose using the Wilcoxon test. The number of
date of onset and disappearance, outcome, and assessment of causal adverse events was compared using Poisson regression. For baseline
relationship to the study drug were investigated at the start of study characteristics, we compared distributions of continuous variables
treatment and at 1, 2, 4, 6, 9, 12, 15, 18, 21, and 24 months after the between groups using the t-test or Wilcoxon test, depending on the
start of study treatment (each within ±2 weeks). shape of the distribution. We analyzed categorical variables using the
chi-squared test or Fisher’s exact test. Posterior probability was
calculated with the improper flat prior and the normal distribution
Outcomes to which log-HR was approximated. Except for noninferiority
The primary end point was defined as the duration from start of testing of the primary end point, we regarded a two-sided P-value
initial treatment to diagnosis of FRNS, or ‘time to FRNS’. Diagnosis o0.05 to indicate statistical significance. We analyzed data using
of FRNS was based on the relapse dates according to the ISKDC. SAS software (version 9.3) and calculated the sample size using the
In our study, FRNS was defined as two relapses within 6 months SAS POWER procedure.
of initial remission (definition 1), or four relapses within any
12-month period (definition 2), which included relapses during DISCLOSURE
initial tapering treatment but excluded relapses with spontaneous This study was supported by a grant from the Ministry of Health,
remissions. Patients were observed for at least 2 years, on the basis of Labour and Welfare, Japan. All expenses were covered by the grant.
the Cochrane review, which states that the risk of relapse after 1–2 NY has received grants from Novartis Pharma K.K. and Asahi Kasei
years was lower after long-term prednisolone treatment relative to Pharma Corporation and has also received lecture fees from Novartis
the ISKDC regimen.8 Relapse was defined as proteinuria 2 þ or Pharma K.K. and Asahi Kasei Pharma Corporation. KN has received
lecture fees from Novartis Pharma K.K. and Asahi Kasei Pharma
higher on dipstick analysis for 3 or more consecutive days or
Corporation. KIs has received lecture fees from Novartis Pharma K.K.
proteinuria 2 þ or higher on dipstick analysis and serum albumin HH has received lecture fees from Asahi Kasei Pharma Corporation.
p25 g/l. Immunosuppressant administration was prohibited in the MH has received lecture fees from Novartis Pharma K.K. and Asahi
protocol. However, if administration was undertaken for clinical Kasei Pharma Corporation. SI has received lecture fees from Novartis
necessity, e.g., steroid dependency, it was treated as an event in the Pharma and Asahi Kasei Pharma Corporation. YS has received lecture
primary analysis. Data for patients who did not experience these fees from Novartis Pharma K.K. HN owns stocks in Asahi Kasei Pharma
events were considered censored at the last examination. Important Corporation. TI has received lecture fees from Takeda Pharmaceutical,

6 Kidney International
N Yoshikawa et al.: RCT for initial prednisolone in childhood NS clinical trial

K.K. KIi has received grants from Takeda Pharmaceutical Co., Ltd., relapsing nephrotic syndrome in children: a multicenter randomized
Asahi Kasei Pharma Corporation, and Novartis Pharma K.K., and phase II trial. Clin J Am Soc Nephrol 2014; 9: 271–278.
16. Kobayashi T, Saji T, Otani T et al. RAISE study group investigators. Efficacy
lecture fees from Novartis Pharma K.K. and Asahi Kasei Pharma
of immunoglobulin plus prednisolone for prevention of coronary artery
Corporation. No other disclosures were reported. abnormalities in severe Kawasaki disease (RAISE study): a randomised,
open-label, blinded-endpoints trial. Lancet 2012; 379: 1613–1620.
ACKNOWLEDGMENTS 17. Nakanishi K, Iijima K, Ishikura K et al. Two-year outcome of the ISKDC
We thank all our patients, their families, and the site investigators. We regimen and frequent-relapsing risk in children with idiopathic nephrotic
thank Emma Barber for editing the article. We thank Drs Jonathan syndrome. Clin J Am Soc Nephrol 2013; 8: 756–762.
18. Mishra OP, Thakur N, Mishra RN et al. Prolonged versus standard
Craig, Patrick Niaudet, and Tohru Kobayashi for their helpful advice.
prednisolone therapy for initial episode of idiopathic nephrotic
The trial was supported by a grant from the Ministry of Health, syndrome. J Nephrol 2012; 25: 394–400.
Labour and Welfare, Japan (H19-shouni-002). The results of this trial 19. Hiraoka M, Tsukahara H, Matsubara K et al. A randomized study of two
were presented in abstract form at the annual meeting of the long-course prednisolone regimens for nephrotic syndrome in children.
American Society of Nephrology, November 7–10, 2013, Atlanta, USA. Am J Kidney Dis 2003; 4: 1155–1162.
This trial is registered at the University Hospital Medical Information 20. Yoshikawa N, Ito H, Takehoshi Y et al. Standard versus long-term
Network clinical trial registry (UMIN-CTR) (http://www.umin.ac. prednisolone with Sairei-to in childhood steroid-responsive nephrotic
syndrome: a prospective controlled study. Jpn J Nephrol 1998; 40:
jp/ctr/), registration number UMIN000000747. See the Supplementary
587–590.
Information online for complete Methods (Clinical Study Protocol).

SUPPLEMENTARY MATERIAL APPENDIX


Figure S2. (A) Meta-analysis of studies comparing 2–3 months Japanese Study Group of Kidney Disease in Children (JSKDC).
of prednisolone to 5–6 months of prednisolone for children with JSKDC has been supported by grants from the Ministry of
their first episode of nephrotic syndrome, with an outcome showing
Health, Labour and Welfare, Japan. Members of the JSKDC
the number of children with frequent relapses after 1–2 years.
(B) Sensitivity analysis excluding Sharma 2002 (unpublished are as follows.
conference proceeding) from Fig. A. Steering Committee: Norishige Yoshikawa (chair), Kazumoto
Supplementary material is linked to the online version of the paper at Iijima, Hidefumi Nakamura, Masataka Honda, and Mayumi
http://www.nature.com/ki Sako.
JSKDC study office: Koichi Nakanishi (chair) and Yuko
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Kidney International 7
clinical trial N Yoshikawa et al.: RCT for initial prednisolone in childhood NS

Kenichiro Miura (The University of Tokyo Hospital), Atsushi Shimizu (Sakai City Hospital), Katsuhisa Yamamoto (Minoh
Inatomi (Yaizu City Hospital), Yoshiyuki Otomo (Juntendo City Hospital), Shinichi Sumimoto (Osaka Red Cross
University Nerima Hospital), Tomonosuke Someya (Juntendo Hospital), Koichi Nakanishi (Wakayama Medical University
University Hospital), Shoichi Oyama (Saiseikai Kawaguchi Hospital), Noriyuki Aoyagi (Wakayama Rosai Hospital), Seiji
General Hospital), Hiroshi Hataya and Kenji Ishikura (Tokyo Iwahashi (Hidaka General Hospital), Masakazu Miyawaki
Metropolitan Children’s Medical Center), Takeshi Matsuyama (Social Insurance Kinan Hospital), Ritsuko Miyashita
(Fussa Hospital), Masahiro Banba (Yokosuka Kyosai Hospi- (Izumiotsu Municipal Hospital), Masamitsu Nishino (Takat-
tal), Kiyoshi Araki (Saitama Social Insurance Hospital), suki General Hospital), Daisuke Hata (Kitano Hospital),
Hitoshi Wakaki (Yokohama City Hospital), Cho Hideo Mikio Goto (Kishiwada City Hospital), Ryojiro Tanaka
(Kawasaki Municipal Hospital), Tomonori Harada (Yokohama (Hyogo Children’s Hospital), Kandai Nozu and Hiroshi Kaito
City University Medical Center), Tomoko Nakamura (Oda- (Kobe University Hospital), Sakiko Konohana (Ono Munici-
wara Municipal Hospital), Shoko Goto (Saiseikai Yokohama pal Hospital), Ichiro Kamioka (Kakogawa City Hospital),
City Nanbu Hospital), Fumio Niimura (Tokai University Masayuki Yamane (Saiseikai Hyogoken Hospital), Katsuji
Hospital), Naohiro Wada (Shizuoka Children’s Hospital), Kuwakado (Kurashiki Central Hospital), Shoji Kagami
Masami Shirai (Iwata City Hospital), Kozo Muto (Shimada (Tokushima University Hospital), Yuhei Ito (Kurume
Municipal Hospital), Osamu Uemura (Aichi Children’s Health University Medical Center), Yoshihiko Murakami (Omuta
and Medical Center), Yoshimitsu Goto (Japanese Red Cross City Hospital), Jiro Iwamoto (Iizuka Hospital), Yoshitsugu
Nagoya Daini Hospital), Naoya Fujita (Seirei Hamamatsu Kaku (Fukuoka Children’s Hospital & Medical Center for
General Hospital), Kazuhide Ohta (National Hospital Orga- Infectious Diseases), Kentaro Kamesaki (Kokuritsukokura
nization Kanazawa Medical Center), Masaki Shimizu (Kana- Hospital), Ken Hatae (Japanese Red Cross Fukuoka Hospital),
zawa University Hospital), Koichi Tsukahara (Fukui University Hitoshi Nakazato (Kumamoto University Hospital), Yasushi
Hospital), Yukiko Mori (Fukui Red Cross Hospital), Hiroshi Otsuka (Saga University Hospital), Tomohiro Ichimaru
Akutagawa (Hyogo Prefectural Tsukaguchi Hospital), Toshi- (Saga-ken Medical Centre Koseikan), and Tadashi Sato
hiro Sawai (Shiga University of Medical Science Hospital), (National Hospital Organization Ureshino Medical Center).
Kashiro Nishizawa (Omihachiman City Hospital), Akira
Ashida (Osaka Medical College Hospital), Naohisa Kawamura
(Osaka Rosai Hospital), Takuya Tanabe (Hirakata City This work is licensed under a Creative Commons
Hospital), Koji Taira (Nara Prefectural Nara Hospital), Seiji Attribution-NonCommercial-NoDerivs 3.0 Un-
Kinoshita (Higashi-Osaka City General Hospital), Shinya ported License. To view a copy of this license, visit http://
Tanaka (Hyogo Prefectural Nishinomiya Hospital), Nobuhiko creativecommons.org/licenses/by-nc-nd/3.0/

8 Kidney International