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

Abstract

In this multicenter, open-label, randomized controlled trial, we determined whether 2-month prednisolone therapy for steroid-sensitive nephrotic syndrome was inferior or not to 6-month therapy despite significantly less steroid exposure. The primary end point was time from start of initial treatment to start of frequently relapsing nephrotic syndrome. The pre-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 were eligible for final analysis. The total prednisolone exposure counted both initial and relapse prednisolone treatment administered over 24 months. Median follow-up in months was 36.7 in the 2-month and 38.2 in the 6-month treatment group. Time to frequent relaps was similar in both groups; however, the median was reached only in the 6-month group (799 days). The hazard ratio was 0.86 (90% confidence interval, 0.64–1.16) and met the non-inferior margin. Time to first relapse was also similar in both groups: median day 242 (2-month) and 243 (6-month). Frequency and severity of adverse events were similar in both groups. Most adverse events were transient and occurred during initial or relapse therapy. Thus, 2 months of initial prednisolone therapy for steroid-sensitive nephrotic syndrome, despite less prednisolone exposure, is not inferior to 6 months of initial therapy in terms of time to onset of frequently relapsing nephrotic syndrome. In this multicenter, open-label, randomized controlled trial, we determined whether 2-month prednisolone therapy for steroid-sensitive nephrotic syndrome was inferior or not to 6-month therapy despite significantly less steroid exposure. The primary end point was time from start of initial treatment to start of frequently relapsing nephrotic syndrome. The pre-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 were eligible for final analysis. The total prednisolone exposure counted both initial and relapse prednisolone treatment administered over 24 months. Median follow-up in months was 36.7 in the 2-month and 38.2 in the 6-month treatment group. Time to frequent relaps was similar in both groups; however, the median was reached only in the 6-month group (799 days). The hazard ratio was 0.86 (90% confidence interval, 0.64–1.16) and met the non-inferior margin. Time to first relapse was also similar in both groups: median day 242 (2-month) and 243 (6-month). Frequency and severity of adverse events were similar in both groups. Most adverse events were transient and occurred during initial or relapse therapy. Thus, 2 months of initial prednisolone therapy for steroid-sensitive nephrotic syndrome, despite less prednisolone exposure, is not inferior to 6 months of initial therapy in terms of time to onset of frequently relapsing nephrotic syndrome. Idiopathic nephrotic syndrome (NS) is a disorder affecting the kidneys that is mainly characterized by high excretion of protein in the urine. Pediatric idiopathic NS is understood to be the most common cause of primary glomerular diseases, and it frequently occurs in infants aged 2–6 years. Most patients are presumed to have minor glomerular abnormality. Cellular immunologic abnormalities are believed to contribute to the condition, although its pathology remains unknown. In Europe and the United States, two in 100,000 children will develop idiopathic NS in a single year.1.Schlesinger E.R. Sultz H.A. Mosher W.E. et al.The nephrotic syndrome: its incidence and implications for the community.Am J Dis Child. 1968; 116: 623-632Crossref PubMed Scopus (73) Google Scholar An 8-week corticosteroid regimen is the standard initial treatment for children with idiopathic NS, as outlined by the International Study of Kidney Disease in Children (ISKDC).2.van Husen M. Kemper M.J. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome.Pediatr Nephrol. 2011; 26: 881-892Crossref PubMed Scopus (92) Google Scholar, 3.Tarshish P. Tobin J.N. Bernstein J. et al.Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children.J Am Soc Nephrol. 1997; 8: 769-776PubMed Google Scholar Although corticosteroids induce the remission of proteinuria in more than 80% of children with idiopathic NS, ∼60% undergo proteinuria relapse. Previous research has shown that a high number of children undergo frequent relapse, and corticosteroid toxicities occur after repeated therapy.2.van Husen M. Kemper M.J. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome.Pediatr Nephrol. 2011; 26: 881-892Crossref PubMed Scopus (92) Google Scholar, 3.Tarshish P. Tobin J.N. Bernstein J. et al.Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children.J Am Soc Nephrol. 1997; 8: 769-776PubMed Google Scholar Although some controlled studies4.Ueda N. Chihara M. Kawaguchi S. et al.Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome.J Pediatr. 1988; 112: 122-126Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 5.Ehrich J.H. Brodehl J. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft für Pädiatrische Nephrologie.Eur J Pediatr. 1993; 152: 357-361Crossref PubMed Scopus (181) Google Scholar, 6.Ksiazek J. Wyszyńska T. Short versus long initial prednisone treatment in steroid-sensitive nephrotic syndrome in children.Acta Paediatr. 1995; 84: 889-893Crossref PubMed Scopus (63) Google Scholar, 7.Bagga A. Hari P. Srivastava R.N. Prolonged versus standard prednisolone therapy for initial episode of nephrotic syndrome.Pediatr Nephrol. 1999; 13: 824-827Crossref PubMed Scopus (70) Google Scholar show that long-term corticosteroid treatment up to 7 months maximum leads to a longer sustained remission of NS than ISKDC-recommended administration, the optimum dose and duration of initial therapy are still unknown. A Cochrane review concluded that a well-designed and adequately powered randomized controlled trial is required to establish the optimum dose and duration of treatment.8.Hodson E.M. Willis N.S. Craig J.C. Corticosteroid therapy for nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 4: CD001533Google Scholar The purpose of this study is to investigate whether 2 months of initial prednisolone therapy (ISKDC regimen) is not inferior to 6 months of initial therapy with an increasing cumulative dose, and to compare adverse events between treatment regimens. The study was conducted from September 6, 2007 until February 8, 2013. Figure 1 shows the trial profile. We assessed 255 patients from 90 hospitals (61 general, 7 children’s, and 22 university hospitals) for eligibility. We randomly assigned 128 patients to the 2-month prednisolone group and 127 patients to the 6-month prednisolone group. We excluded nine patients from the analysis: six did not receive trial medication because of either early relapse after remission during the initial 4-week prednisolone treatment, or withdrawn consent, and three were excluded owing to a lack of participant data. Thus, we analyzed data for 246 patients. Median follow-up was 36.7 months in the 2-month group (interquartile range 27.8–46.4 months) and 38.2 months in the 6-month group (interquartile range 28.6–48.5 months). There was no difference in characteristics between the two groups (Table 1).Table 1Baseline characteristics2-Month prednisolone (n=124)6-Month prednisolone (n=122)P-valueMale, n (%)89 (71.8)87 (71.3)0.94Age, mean (s.d.), years6.7 (4.1)6.3 (4.1)0.42Age 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.), mmHg Systolic104.4 (10.7)106.4 (12.0)0.16 Diastolic62.4 (10.0)62.5 (11.3)0.98Serum albumin, mean (s.d.), g/l1.4 (0.5)1.4 (0.5)0.90Hospital, n (%) General47 (65.3)46 (64.8)1.00 Children’s7 (9.7)7 (9.9) University18 (25.0)18 (25.4)Quarterly distribution of disease onset, n (%) January–March23 (18.7)24 (19.7)0.99 April–June36 (29.3)34 (27.9) July–September30 (24.4)31 (25.4) October–December34 (27.6)33 (27.0)Duration from the first episode to remission, mean (s.d.), days9.7 (3.1)10.0 (3.1)0.45Abbreviation: s.d., standard deviation. Open table in a new tab Abbreviation: s.d., standard deviation. The primary end point was defined as the duration from start of initial treatment to diagnosis of frequently relapsing nephrotic syndrome (FRNS), or ‘time to FRNS’. By the end of the 24-month intervention period, we observed 54 events in the 2-month group (comprising 46 FRNS [definition 1, 28; definition 2, 18], and 8 requiring immunosuppressant administration) and 58 events in the 6-month group (comprising 45 FRNS [definition 1, 23; definition 2, 22], and 13 requiring immunosuppressant administration). Twenty-one patients required immunosuppressants owing to steroid-dependent or steroid-resistant relapse. Times to FRNS were similar in both groups: however, the median duration of time to FRNS was reached only in the 6-month group (at 799 days). The hazard ratio (HR) was 0.86 (90% confidence interval (CI), 0.64–1.16; Figure 2), and noninferiority of the 2-month group was confirmed significantly, with an HR margin of 1.3 (P=0.01). Post-hoc analyses showed that age groups did not affect the median duration of time to FRNS. The HRs (95% CI) were 0.92 (0.59–1.45), 0.86 (0.41–1.84), and 0.74 (0.31–1.77) for the age groups 1–5 years, 6–10 years, and 11–15 years, respectively. Times to first relapse were similar in both groups: the median was 242 days and 243 days in the 2-month and 6-month treatment groups, respectively (HR=0.97; 95% CI, 0.72–1.31; P=0.86; Figure 3). The number of relapses per person-year during the trial intervention period was 1.25 times in the 2-month group and 1.33 times in the 6-month group, and the ratio was 0.94 (95% CI, 0.71–1.22; P=0.65, Table 2). The median cumulative dose of prednisolone during the 2-year trial period in the 2-month group was also significantly lower than in the 6-month group (4621.9 [interquartile range=2191.3–7472.5] vs. 6484.8 [interquartile range=3701.0–9577.9], P<0.001).Table 2Number of relapsesTotal number of relapsesDuration of observation (person-year)The number of relapses (per person-year)Ratio of the number of relapses (CI)P-value2-Month prednisolone301240.931.250.940.656-Month prednisolone309232.621.33(0.71–1.22)Abbreviation: CI, confidence interval. Open table in a new tab Abbreviation: CI, confidence interval. Frequency and severity of adverse events were similar in both groups (Table 3). Most adverse events were transient and occurred during initial therapy or relapse therapy. In our study, steroid dependency did not greatly affect the occurrence of adverse events. Two patients in the 2-month group had severe adverse events requiring hospitalization. One patient discontinued because of acute kidney failure during relapse (month 10) and recovered in 22 days. Another patient had pneumonia with influenza infection on the last date of the 2-month prednisolone treatment and recovered in 10 days. Height standard deviation scores show a significant decrease in growth at 2 months of follow-up compared with baseline (P<0.003). In both groups, this was restored within 9 months after initial treatment commenced. Notably, one patient in the 6-month group was diagnosed with possible adrenal insufficiency owing to steroid withdrawal according to clinical symptoms (mild headache and mild nausea) when the patient switched to trial medication after the initial dose of prednisolone. Symptoms disappeared on the same day of onset without further treatment.Table 3Adverse events during the 24-month trial intervention periodaData are expressed as the number of events.Event2-Month prednisolone n=1246-Month prednisolone n=122P-valueHypertensionbMultiple reports were recorded for these adverse events.1590.24Cushingoid appearance Cushing (moon face)bMultiple reports were recorded for these adverse events.54610.46 Central obesitybMultiple reports were recorded for these adverse events.20340.052 Striae101.00Adrenal insufficiency011.00Ophthalmological abnormalities GlaucomabMultiple reports were recorded for these adverse events.19130.31 Cataract00Severe infections PneumoniacSevere adverse events requiring hospitalization.101.00Peptic ulcer101.00Acute kidney failurecSevere adverse events requiring data reports were recorded for these adverse reports were recorded for these adverse are expressed as the number of reports were recorded for these adverse adverse events requiring hospitalization. Open table in a new tab of initial steroid treatment for more than months to decrease the of relapse in children with steroid-sensitive NS has in N. Chihara M. Kawaguchi S. et al.Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome.J Pediatr. 1988; 112: 122-126Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 5.Ehrich J.H. Brodehl J. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft für Pädiatrische Nephrologie.Eur J Pediatr. 1993; 152: 357-361Crossref PubMed Scopus (181) Google Scholar, 6.Ksiazek J. Wyszyńska T. Short versus long initial prednisone treatment in steroid-sensitive nephrotic syndrome in children.Acta Paediatr. 1995; 84: 889-893Crossref PubMed Scopus (63) Google Scholar, 7.Bagga A. Hari P. Srivastava R.N. Prolonged versus standard prednisolone therapy for initial episode of nephrotic syndrome.Pediatr Nephrol. 1999; 13: 824-827Crossref PubMed Scopus (70) Google Scholar, E.M. Willis N.S. Craig J.C. Corticosteroid therapy for nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 4: CD001533Google Scholar, E.M. and of steroid-sensitive nephrotic Pediatr. PubMed Scopus Google Scholar, E.M. Craig J.C. Willis N.S. of steroid-sensitive nephrotic syndrome.Pediatr Nephrol. PubMed Scopus Google Scholar of children diagnosed with are new corticosteroid to relapse, and relapse E.M. Willis N.S. Craig J.C. treatment for nephrotic syndrome in children.Cochrane Database Syst Rev. Scholar initial to therapy are to be N. et of nephrotic syndrome.Pediatr Nephrol. PubMed Scopus Google Scholar that initial steroid treatment, and increasing the total dose of prednisolone vs. not clinical to time to first relapse, the number of total prednisolone dose, and adverse for to the Cochrane review by et E.M. Willis N.S. Craig J.C. Corticosteroid therapy for nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 4: CD001533Google Scholar by treatment of 2 vs. 6 months. on a study from the trial of children with NS showed no in clinical when the initial prednisolone treatment was from to 6 months without an increasing cumulative N. J. N. et prednisolone therapy not relapse in nephrotic syndrome.J Am Soc Nephrol. PubMed Scopus Google Scholar despite the of this trial, the most duration and of prednisolone treatment for an initial episode of is still E.M. Craig J.C. Corticosteroid therapy for steroid-sensitive nephrotic syndrome in dose or Am Soc Nephrol. PubMed Scopus Google Scholar Although our study has that increasing the total dose in 2-month or 6-month not clinical further is still required to the most duration and regimen for initial A of our trial is its is a multicenter, controlled trial for noninferiority that the of the 2-month regimen with a long-term prednisolone The most clinical of initial treatment of is to frequent the primary end point was to time to FRNS than initial data from analyses noninferiority of the In the trial, a HR of 1.3 for noninferiority of the primary end point is high the study the that a HR be than and that are as an was and respectively. In our trial, noninferiority was in FRNS end and first relapse end between the and 6-month regimens. that patients relapse prednisolone 3). Previous in observation of relapses from either the start or end of initial E.M. Willis N.S. Craig J.C. Corticosteroid therapy for nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 4: CD001533Google Scholar, N. J. N. et prednisolone therapy not relapse in nephrotic syndrome.J Am Soc Nephrol. PubMed Scopus Google Scholar analyses are from the end of initial relapses during prednisolone be in an we from the start of initial therapy. In our study steroid-dependent NS was to occur more frequently because of its definition in the 6-month is one we FRNS as a primary end and not steroid-dependent In time to steroid-dependent NS was significantly in the regimen group not significant difference in adverse events was observed between the two in our trial, which is a similar to N. Chihara M. Kawaguchi S. et al.Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome.J Pediatr. 1988; 112: 122-126Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 5.Ehrich J.H. Brodehl J. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft für Pädiatrische Nephrologie.Eur J Pediatr. 1993; 152: 357-361Crossref PubMed Scopus (181) Google Scholar, 6.Ksiazek J. Wyszyńska T. Short versus long initial prednisone treatment in steroid-sensitive nephrotic syndrome in children.Acta Paediatr. 1995; 84: 889-893Crossref PubMed Scopus (63) Google Scholar, 7.Bagga A. Hari P. Srivastava R.N. Prolonged versus standard prednisolone therapy for initial episode of nephrotic syndrome.Pediatr Nephrol. 1999; 13: 824-827Crossref PubMed Scopus (70) Google Scholar Most adverse events were transient and occurred during initial or relapse therapy. because the regimen is less to cause adverse events owing to the lower and the its be A of our trial is the which have as our trial is a noninferiority trial with and relapses are we the of this study have on the of this trial be to the high of relapse compared with J.H. Brodehl J. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft für Pädiatrische Nephrologie.Eur J Pediatr. 1993; 152: 357-361Crossref PubMed Scopus (181) Google Scholar The high of relapse be owing to our definition of relapse or still remains whether long prednisolone therapy of a dose of per day for 6 by of per 2 days for 6 is more time to FRNS compared with the regimen for idiopathic In our study, only one patient A of withdrawal is common in M. et Study of Kidney Disease in for the treatment of frequently relapsing nephrotic syndrome in a randomized J Am Soc Nephrol. PubMed Scopus Google Scholar, T. T. T. et study group of prednisolone for of abnormalities in severe disease a open-label, Full Text Full Text PDF PubMed Scopus Google Scholar between for in of In our study, steroid was confirmed by day in to time for remission after is et of the regimen and in children with idiopathic nephrotic J Am Soc Nephrol. 8: PubMed Scopus Google Scholar as the of early of steroid was we to steroid by day We conducted a to the between corticosteroid in children with an initial episode of We randomized controlled that compared of steroid therapy in children and the number of FRNS within 2 years the for a of our study and J. Wyszyńska T. Short versus long initial prednisone treatment in steroid-sensitive nephrotic syndrome in children.Acta Paediatr. 1995; 84: 889-893Crossref PubMed Scopus (63) Google Scholar, N. J. N. et prednisolone therapy not relapse in nephrotic syndrome.J Am Soc Nephrol. PubMed Scopus Google Scholar, N. R.N. et versus standard prednisolone therapy for initial episode of idiopathic nephrotic syndrome.J Nephrol. PubMed Scopus Google Scholar, M. et randomized study of two prednisolone for nephrotic syndrome in J Kidney 4: Full Text Full Text PDF Scopus Google Scholar showed a ratio of (95% CI, Figure of our study and the only showed an ratio of (95% Figure that long-term treatment is not to therapy. with with In our study shows that initial prednisolone treatment from 2 to 6 months with an increasing dose not clinical for The regimen is not inferior to 6 months of initial therapy with an increasing cumulative We that the regimen is as an initial treatment for idiopathic We conducted a multicenter, trial at 90 hospitals in and compared prednisolone treatment of 2 months (ISKDC regimen) with 6 months for children with a first episode of idiopathic We diagnosed idiopathic NS and remission according to the E.R. Sultz H.A. Mosher W.E. et al.The nephrotic syndrome: its incidence and implications for the community.Am J Dis Child. 1968; 116: 623-632Crossref PubMed Scopus (73) Google Scholar NS was defined as a ratio and in was defined as a for days. aged years with a first episode of idiopathic NS were eligible had remission within of prednisolone were had NS, insufficiency defined as of per controlled severe or a of immunosuppressant consent, and was from children. study was by the review of with the of and the of and to the International on on were randomly assigned to either the 2-month or 6-month group in a ratio at the We a a with age years or 11–15 and as and and data were not to the treatment from the trial and the and to the trial until follow-up was The first patient was randomized in September and the last patient in at diagnosis and was when the last patients the 24-month patients diagnosed with a first episode of idiopathic NS initial therapy of prednisolone in three of for a and were after remission, was switched to trial medication after initial of prednisolone were after remission during the initial 4-week prednisolone treatment, were medication of initial treatment and relapse treatment, and was within a total of 24 months in both groups and The duration of long-term prednisolone treatment was to 6 which is with from a randomized controlled E.M. Willis N.S. Craig J.C. Corticosteroid therapy for nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 4: CD001533Google Scholar The cumulative dose of initial treatment was and during the 24-month trial medication period relapse treatment treatment was the same in both groups. relapse treatment during the 6-month initial treatment was according to the initial treatment regimen in the 6-month group. characteristics and were recorded at and and were at 1, 2, and 6 months after and months and also on diagnosis of relapse. was at 1, 2, 6, and months after at the end of treatment, and at diagnosis of relapse events were recorded the trial period and assessed for of initial treatment, were for by an adverse events are in the of date of onset and and of to the study were at the start of study treatment and at 1, 2, 6, and 24 months after the start of study treatment within The primary end point was defined as the duration from start of initial treatment to diagnosis of or ‘time to FRNS’. of FRNS was on the relapse according to the In our study, FRNS was defined as two relapses within 6 months of initial remission or relapses within period 2), which relapses during initial tapering treatment excluded relapses with were observed for at 2 years, on the of the Cochrane which that the of relapse after years was lower after long-term prednisolone treatment to the E.M. Willis N.S. Craig J.C. Corticosteroid therapy for nephrotic syndrome in children.Cochrane Database Syst Rev. 2010; 4: CD001533Google Scholar was defined as proteinuria or on for or more days or proteinuria or on and was in the was for clinical steroid it was as an in the primary analysis. for patients did not these events were at the last end were time to first relapse, the number of relapses per total prednisolone dose, and adverse events. The primary of this trial was to noninferiority of initial therapy with 2-month treatment compared with 6-month treatment, with to time to FRNS. The noninferiority margin of HR for the 2-month to 6-month group was to and the significance was to The was determined on conducted and the was the of from a N. et versus long-term prednisolone with in nephrotic syndrome: a controlled J Nephrol. Scholar we an of and at 1 in the and 6-month groups, respectively. a of patients in treatment group, an HR with a one-sided significance have to and follow-up times were to be and 2 years, respectively. the N. et versus long-term prednisolone with in nephrotic syndrome: a controlled J Nephrol. Scholar was conducted more than 10 years it is possible that the of our study is lower than the We an to the which was in A the primary end point was not The number of events observed that of the and the study was not analyses the and the The hazard was to noninferiority and the HR with a of the primary end The was to time to FRNS. and the were to time to first relapse. The number of relapses per person-year was as the total number of relapses by the total observed in treatment group (Table 2). A was to compare the number of relapses per person-year between groups. We compared the prednisolone total dose the The number of adverse events was compared baseline we compared of between groups the or on the of the We analyzed the or was with the and the distribution to which was for noninferiority of the primary end we a to We analyzed data and the the Study of Kidney Disease in Children has by from the of and of the are as and study and and and Central and for and of Kawaguchi and and of and Central for and We our and the We for the We and for The trial was by a from the of and The of this trial were in at the of the of trial is at the clinical trial number the for Study Figure of months of prednisolone to months of prednisolone for children with first episode of nephrotic syndrome, with an the number of children with frequent relapses after years. from A. is to the of the at is a a of this of glomerular clinical will be the of the International of Kidney International has that have clinical its The of has to significant in patient in the PDF