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A multicenter randomized trial indicates initial prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-month treatment

& 2014 International Society of Nephrology A multicenter randomized trial indicates initialprednisolone treatment for childhood nephroticsyndrome for two months is not inferior tosix-month treatmentNorishige 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 theJapanese Study Group of Kidney Disease in Children10 1Department 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 Schoolof Medicine, Yokohama City University, Yokohama, Japan; 4Department of Health Policy, National Center for Child Health andDevelopment, Tokyo, Japan; 5Department of Nephrology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan; 6Departmentof 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 and9Department 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.
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 withone-sided significance of 5%. We randomly assigned 255children with an initial episode of steroid-sensitive nephroticsyndrome 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 yearAn 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).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 researchhas 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.
therapyAlthough some controlled studiesand a meta- ashow that long-term corticosteroid treatment up to 10See 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

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 treatme 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; and noninfer- treatment regimens.
iority of the 2-month group was confirmed significantly, withan HR margin of 1.3 (P ¼ 0.01). Post-hoc analyses showed 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. shows the trial profile. We assessed 6–10 years, and 11–15 years, respectively.
255 patients from 90 hospitals (61 general, 7 children's, and22 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 medication because of either early relapse after remission 0.72–1.31; P ¼ 0.86; 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 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- quartile range ¼ 3701.0–9577.9], Po0.001).
Primary end point 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 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 2 Early relapse after remission 3 Early relapse after remission during the initial 4-week during the initial 4-week 1 Withdrew consent before 1 No follow-up data available allocated trial medication 2 No follow-up data available 124 Patients analyzed 122 Patients analyzed Figure 1 Trial profile.
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N Yoshikawa et al.: RCT for initial prednisolone in childhood NS Table 1 Baseline characteristics 2-Month prednisolone (n ¼ 124) 6-Month prednisolone (n ¼ 122) Age, mean (s.d.), years Blood pressure, mean (s.d.), mm Hg Serum albumin, mean (s.d.), g/l Quarterly distribution of disease onset, n (%) Duration from the first episode to remission, mean (s.d.), days Abbreviation: s.d., standard deviation.
HR for FRNS: 0.86 (90% Cl, 0.64–1.16) HR for times to first relapse: 0.97 (95% Cl, 0.72–1.31; P =0.86) Non-inferiority with HR margin 1.3 of 2-month group: P = 0.01 Relapse-free rate 0.3 2-Month prednisolone Non- frequent relapse rate 2-Month prednisolone 6-Month prednisolone 6-Month prednisolone 2-Month group 124 2-Month group 124 6-Month group 122 6-Month group 122 Figure 2 Kaplan–Meier estimates of time to frequently relapsingnephrotic 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 in10 days. Height standard deviation scores show a significant 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 studHowever, 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.Therefore, initial the patient switched to trial medication after the initial dose approaches to SSNS therapy are likely to be substantially Kidney International N Yoshikawa et al.: RCT for initial prednisolone in childhood NS Table 2 Number of relapses Duration of observation The number of relapses Ratio of the number (per person-year) 2-Month prednisolone 6-Month prednisolone 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.
A key strength of our trial is its unique design. This is a multicenter, randomized, controlled trial for noninferiority that compares the efficacy of the 2-month ISKDC regimen with a 6-month, long-term prednisolone regimen. The mostimportant clinical objective of initial treatment of SSNS is to Cushingoid appearance prevent frequent relapses. Consequently, the primary end Cushing (moon face)b point was set to time to FRNS rather than initial relapses.
Our data from several analyses consistently support Adrenal insufficiency noninferiority of the ISKDC regimen. In the current trial, aHR threshold of 1.3 for noninferiority of the primary end point is slightly high given the feasible study size. However, the posterior probability that a HR would be smaller than1.1 and 1.2 (HRs that are commonly used as an upper Severe infections equivalence margin) was 91 and 97%, respectively.
In our trial, noninferiority was found in FRNS (primary Acute kidney failurec end point) and first relapse (secondary end point) between the ISKDC and 6-month regimens. This means that manypatients relapse even while taking tapering-dose prednisolone Increased laboratory data (Previous studies vary in their observation of (frequent) relapses from either the start or end of initial therapyHowever, 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.
bMultiple reports were recorded for these adverse events.
cannot be counted, possibly resulting in an inadequate cSevere adverse events requiring hospitalization.
interpretation. Therefore, we selected observations primarilyfrom the start of initial therapy. In our study design, steroid-dependent NS was predicted to occur more frequentlybecause of its definition in the 6-month regimen. This is different.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 comparing treatment regimens similar finding to previous small-scale 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.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.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.The high Kidney International

N Yoshikawa et al.: RCT for initial prednisolone in childhood NS 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 60 mg/m2 per day for 6 weeks, followed by alternate-daydoses of 40 mg/m2 per 2 days for 6 weeks, is more effective 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.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.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 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 strategy). Meta-analysis of our study and five stud 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. Patientsunderwent 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 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.
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 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 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 METHODSStudy design and patientsWe conducted a multicenter, randomized, noninferiority, open-labeltrial at 90 hospitals in Japan and compared prednisolone treatmentof 2 months (ISKDC regimen) with 6 months for children witha first episode of idiopathic NS. We diagnosed idiopathic NS and remission according to the ISKDC.NS was defined as a urinary 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 ofprednisolone administration. Patients were ineligible if they hadsecondary NS, renal insufficiency defined as creatinine clearance ofp60 ml/min per 1.73 m2, active infections, poorly controlledhypertension, severe liver dysfunction, pregnancy, or a history ofimmunosuppressant administration.
Before enrollment, patients' guardians provided written in- formed consent, and informed assent was obtained from older 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.
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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 analysesThe primary objective of this trial was to confirm noninferiority ofinitial therapy with 2-month treatment compared with 6-monthtreatment, with respect to time to FRNS. The noninferiority marginof HR for the 2-month to 6-month group was predefined to 1.3, and the significance level was set to 5% (one-sided). The former 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 negative on 3 consecutive days using a urine dipstick test. Upper On the basis of results from a previous study,we assumed an doses are in mg/m2/day. A maximum dose of each is the same as event rate of 15 and 19% at 1 year in the 2- and 6-month groups, initial treatments in AD, alternate days; D, daily.
respectively. With a sample size of 125 patients in each treatmentgroup, an HR test with a one-sided 5% significance level would have70% 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 Relapse treatment was the As the previous studywas 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 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 thechi-squared test or Fisher's exact test. Posterior probability wascalculated with the improper flat prior and the normal distribution 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 any12-month period (definition 2), which included relapses during 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 Relapse was defined as proteinuria 2 þ or Pharma K.K. and Asahi Kasei Pharma Corporation. KN has receivedlecture 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, Kidney International N Yoshikawa et al.: RCT for initial prednisolone in childhood NS 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.
lecture fees from Novartis Pharma K.K. and Asahi Kasei Pharma Kobayashi T, Saji T, Otani T et al. RAISE study group investigators. Efficacyof 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.
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.
Craig, Patrick Niaudet, and Tohru Kobayashi for their helpful advice.
Mishra OP, Thakur N, Mishra RN et al. Prolonged versus standardprednisolone 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 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 Yoshikawa N, Ito H, Takehoshi Y et al. Standard versus long-term Network clinical trial registry (UMIN-CTR) ( prednisolone with Sairei-to in childhood steroid-responsive nephrotic registration number UMIN000000747. See the Supplementary syndrome: a prospective controlled study. Jpn J Nephrol 1998; 40:587–590.
Information online for complete Methods (Clinical Study Protocol).
SUPPLEMENTARY MATERIAL 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.
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Hodson EM, Craig JC. Corticosteroid therapy for steroid-sensitive General Hospital), Tae Omori (Tokyo Metropolitan Bokutoh nephrotic syndrome in children: dose or duration? J Am Soc Nephrol 2013; Hospital), Nobuyuki Kurosawa (Tsuchiura Kyodo General Hospital), Masuhiro Shimoda (Japanese Red Cross Musashino Iijima K, Sako M, Oba MS et al. Japanese Study Group of Kidney Disease inChildren. Cyclosporine C2 monitoring for the treatment of frequently Kidney International 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 (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 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), AkiraAshida (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 Tanaka (Hyogo Prefectural Nishinomiya Hospital), Nobuhiko Kidney International


REVERSE PAYMENT PATENT SETTLEMENTS IN THE EUROPEAN UNION AND THE UNITED STATES Damien Geradin George Mason University School of Law Douglas Ginsburg George Mason University School of Law Graham Safty University of Chicago Law School George Mason University

Microsoft word - security_guards.docx

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