Hidefumi Nakamura

Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial

BACKGROUND Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity. METHODS We did a multicentre, double-blind, randomised, placebo-controlled trial at nine centres in Japan. We screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1-18 years. Patients with complicated FRNS or SDNS who met all other criteria were eligible for inclusion after remission of the relapse at screening. We used a computer-generated sequence to randomly assign patients (1:1) to receive rituximab (375 mg/m(2)) or placebo once weekly for 4 weeks, with age, institution, treatment history, and the intervals between the previous three relapses as adjustment factors. Patients, guardians, caregivers, physicians, and individuals assessing outcomes were masked to assignments. All patients received standard steroid treatment for the relapse at screening and stopped taking immunosuppressive agents by 169 days after randomisation. Patients were followed up for 1 year. The primary endpoint was the relapse-free period. Safety endpoints were frequency and severity of adverse events. Patients who received their assigned intervention were included in analyses. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000001405. FINDINGS Patients were centrally registered between Nov 13, 2008, and May 19, 2010. Of 52 patients who underwent randomisation, 48 received the assigned intervention (24 were given rituximab and 24 placebo). The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223-374) than in the placebo group (101 days, 70-155; hazard ratio: 0·27, 0·14-0·53; p<0·0001). Ten patients (42%) in the rituximab group and six (25%) in the placebo group had at least one serious adverse event (p=0·36). INTERPRETATION Rituximab is an effective and safe treatment for childhood-onset, complicated FRNS and SDNS. FUNDING Japanese Ministry of Health, Labour and Welfare.

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

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.

Cyclosporine C2 Monitoring for the Treatment of Frequently Relapsing Nephrotic Syndrome in Children: A Multicenter Randomized Phase II Trial

BACKGROUND AND OBJECTIVES An open-label, multicenter, randomized phase II trial was conducted from July 1, 2005 to March 29, 2011 to compare two protocols for treating children with frequently relapsing nephrotic syndrome using microemulsified cyclosporine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Ninety-three children with frequently relapsing nephrotic syndrome were randomly assigned to group A (n=46) or group B (n=47). In both groups, the 2-hour postdose cyclosporine level was monitored. For group A, the cyclosporine target was set to 600-700 ng/ml for the first 6 months and 450-550 ng/ml for the next 18 months; for group B, it was set to 450-550 ng/ml for the first 6 months and 300-400 ng/ml for the next 18 months. The primary end point was the sustained remission rate. At the end of the study, if there was no difference in safety profile between the two groups and the sustained remission rate in group A was superior to group B with a decision threshold of 8%, then the regimen for group A would be determined the better treatment. RESULTS Eight children from an ineligible institution, where cyclosporine levels were not measured, were excluded from all analyses. At 24 months, the sustained remission rate was nonsignificantly higher in group A (n=43) than group B (n=42; 64.4% versus 50.0%; hazard ratio, 0.57; 95% confidence interval, 0.29 to 1.11; P=0.09), and the progression-free survival rate was significantly higher (88.1% versus 68.4%; hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.94; P=0.03). The relapse rate was significantly lower in group A than group B (0.41 versus 0.95 times/person-year; hazard ratio, 0.43; 95% confidence interval, 0.19 to 0.84; P=0.02). The rate and severity of adverse events were similar in both treatment groups. CONCLUSION The sustained remission rate was not significantly different between the two treatment groups, but the regimen with the higher 2-hour postdose cyclosporine level target improved progression-free survival and reduced the relapse rate.

Pharmacokinetics of Carboplatin in a One‐Year‐Old Anuric Boy Undergoing Hemodialysis and a Review of the Literature

There have been few reports of carboplatin‐based chemotherapy for anuric infants. As we had a chance to treat a one‐year‐old anuric hepatoblastoma patient with carboplatin, we performed a pharmacokinetic analysis and examined the optimal treatment strategy. A one‐year‐old anuric boy under peritoneal dialysis was diagnosed with hepatoblastoma. Surgical resection was performed, and administration of carboplatin was scheduled postoperatively aiming at 5 mg·min/mL of the area under the curve from the time of dosing to the time of the last observation (AUC0‐t). We set the initial dose at 50 mg, higher than that calculated by the Calvert formula (34 mg); the time from the end of carboplatin infusion to the initiation of hemodialysis at 2 h; and the hemodialysis duration at 24 h. The actual AUC0‐t was 3.05 mg·min/mL because the elimination half‐lives before and during hemodialysis were shorter than expected. The AUC0‐t after the second dose (100 mg) and the third dose (80 mg) were 7.00 and 4.68 mg·min/mL, respectively. The Calvert formula is not suitable for hemodialysis patients because removal of platinum by hemodialysis is not taken into account. It appears that extrarenal clearance in anuric infants is different from that in adults. We obtained an optimal AUC0‐t using a dose of 80 mg (200 mg/m2), setting the time from the end of carboplatin infusion to the initiation of hemodialysis at 2 h, and performing 8‐h hemodialysis. Further accumulation of the pharmacokinetic data of carboplatin is necessary for anuric children.

Age-Appropriate Pediatric Dosage Forms in Japan: Insights into End-User Perceptions From an Observational Cross-Sectional Survey Assessing the Acceptability of Oral Formulation

Background: The lack of appropriate pediatric formulations is a global issue and information on acceptability is urgently needed to develop standard pediatric formulations. This study aimed to assess perceptions of acceptability of several oral dosage forms among pediatric patients at a community and a pediatric hospital in Japan and collected information about age-appropriate pediatric formulations, aiming to contribute to drug development promotion worldwide. Methods: A cross-sectional observational study was performed. A convenience sample of caregivers was recruited from available chain-owned retail pharmacies and inpatient pediatric units. The questionnaire was composed of 3 parts: (1) acceptability of the 5 dosage forms (tablets, capsules, powders, liquids, and orally disintegrating tablet) by age; (2) acceptability of dosage size, amount, and volume by age; and (3) the actual method of administration. Face-to-face interviews were conducted at 3 independent community pharmacies (324 parents) and tertiary care pediatric hospital wards (112 nursing staff). Acceptability scores and acceptable dosages were then determined. The survey was conducted from October 1 to December 1, 2017, for the hospital setting and November 1 to 30, 2017, for the outpatient setting. Results: The acceptability of oral dosage forms was roughly similar to the matrix drafted by the European Medical Agency. Differences in perception of the powder forms between communities and hospitals were also observed, with the nursing staff perceiving powder as being acceptable from the neonatal period. Conclusions: The difference in caregivers’ perception of the acceptability of oral formulations between Japan and Europe was small. The powder form was found to be more acceptable in Japan. Further intervention studies are needed to assess the preferred pediatric formulation worldwide.

The Japanese experience and pharmacokinetics of antenatal maternal high-dose immunoglobulin treatment as a prophylaxis for neonatal hemochromatosis in siblings

Abstract Background: Neonatal hemochromatosis (NH) is a rare but serious disease causing fulminant hepatic failure. The recurrence rate of NH in a subsequent infant of a mother with an affected infant is 70–90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) treatment has been reported to be effective for preventing NH recurrence. However, data on the IgG concentrations during this treatment are limited. Objective: We report a Japanese experience and present a pharmacokinetic simulation model of IgG during IVIG treatment. Methods: Women with histories of pregnancy diagnosed with NH were treated with IVIG weekly from the second trimester until the end of gestation. Serum IgG levels during treatment were collected frequently and pharmacokinetics were simulated by a two-compartment model. Results: Six women were included during eight pregnancies. None experienced severe adverse events. Three out of eight infants showed temporary liver dysfunction, but none required any treatment. A simulation study showed that the estimated trough and peak levels of IgG concentrations during IVIG were 2000–3000 and 4000–5000 mg/dl, respectively. Conclusion: This treatment prevented the recurrence of NH in siblings in Japanese women. We examined the details of serum IgG concentrations and introduced a new pharmacokinetic simulation model of IgG concentrations during IVIG treatment.

Rituximab for patients with nephrotic syndrome – Authors' reply

226 www.thelancet.com Vol 385 January 17, 2015 2 Van Vollenhoven R, Emery P, Bingham CO, et al. Long term safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol 2010; 37: 558–67. 3 Van Vollenhoven RF, Emery P, Bingham CO, et al. Long term safety of rituximab in rheumatoid arthritis: 9·5 year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 2013; 72: 1496–502. 4 Diwakar L, Gorrie S, Richter A, et al. Does rituximab aggravate pre-existing hypogammaglobulinaemia? J Clin Pathol 2010; 63: 275–77. 5 Kaplan B, Kopyltsova Y, Khokhar A, et al. Rituximab and immune defi ciency: case series and review of the literature. J Allergy Clin Immunol Pract 2014; 2: 594–600. 4 Gottenberg JE, Ravaud P, Bardin T, et al. Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 2010; 62: 2625–32. 5 Cravedi P, Ruggenenti P, Sghirlanzoni MC, Remuzzi G. Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 2007; 2: 932–37. treatment. Cyclophosphamide can lead to long-term remission and is recommended for childhood nephrotic syndrome as a first-line therapy. In patients with an inadequate response to this drug, rituximab should be considered as a treatment option. We would appreciate if Iijima and colleagues could provide information about the treatment of the placebo group, since the number of infusion reactions (26 times) was particularly high. Moreover, some of the reported adverse events in the rituximab group are potentially life-threatening, such as respiratory disturbance or acute kidney failure. We believe that there is a strong need to monitor levels of immunoglobulin because persistent hypogammaglobulinaemia, despite complete remission, might be a crucial variable aff ecting risk of infection. Dose reduction of rituximab might be feasible since most patients receiving a single dose had a long lasting peripheral B-cell depletion and only one patient needed a second dose to achieve complete depletion. In terms of cost-saving and reduction of infectious risks, the lowest effective dose of rituximab needs to be established.