title: Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  Rituximab is an effective and safe treatment for childhood-onset, complicated FRNS and SDNS.
  
  
  BACKGROUND
  Japanese Ministry of Health, Labour and Welfare.
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan. Electronic address: iijima@med.kobe-u.ac.jp.
authors: Kazumoto
authors: K
authors: Iijima
authors: Division for Clinical Trials, Department of Development Strategy, Center for Social and Clinical Research, National Research Institute for Child Health and Development, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors: Mayumi
authors: M
authors: Sako
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors: Kandai
authors: K
authors: Nozu
authors: Department of Health Policy, Center for Social and Clinical Research, National Research Institute for Child Health and Development, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors: Rintaro
authors: R
authors: Mori
authors: Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors: Nao
authors: N
authors: Tuchida
authors: Department of Nephrology and Rheumatology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors: Koichi
authors: K
authors: Kamei
authors: Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors: Kenichiro
authors: K
authors: Miura
authors: Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan.
authors: Kunihiko
authors: K
authors: Aya
authors: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors: Koichi
authors: K
authors: Nakanishi
authors: Department of Pediatrics, Juntendo University Nerima Hospital, Nerima-ku, Tokyo, Japan.
authors: Yoshiyuki
authors: Y
authors: Ohtomo
authors: Department of Pediatrics, Surugadai Nihon University Hospital, Chiyoda-ku, Tokyo, Japan.
authors: Shori
authors: S
authors: Takahashi
authors: Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, Suma-Ku, Kobe, Japan.
authors: Ryojiro
authors: R
authors: Tanaka
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors: Hiroshi
authors: H
authors: Kaito
authors: Division for Clinical Trials, Department of Development Strategy, Center for Social and Clinical Research, National Research Institute for Child Health and Development, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors: Hidefumi
authors: H
authors: Nakamura
authors: Department of Nephrology, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.
authors: Kenji
authors: K
authors: Ishikura
authors: Department of Nephrology and Rheumatology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors: Shuichi
authors: S
authors: Ito
authors: Chuo University, Bunkyo-ku, Tokyo, Japan.
authors: Yasuo
authors: Y
authors: Ohashi
mesh_terms: D000293:Adolescent; D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D008297:Male; D009404:Nephrotic Syndrome / Q000188:drug therapy* / Q000276:immunology; D011239:Prednisolone / Q000627:therapeutic use; D012008:Recurrence; D000069283:Rituximab; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000069283:Rituximab; D011239:Prednisolone