Kazumoto Iijima1, Mayumi Sako2, Kandai Nozu3, Rintaro Mori4, Nao Tuchida5, Koichi Kamei6, Kenichiro Miura7, Kunihiko Aya8, Koichi Nakanishi9, Yoshiyuki Ohtomo10, Shori Takahashi11, Ryojiro Tanaka12, Hiroshi Kaito3, Hidefumi Nakamura2, Kenji Ishikura13, Shuichi Ito6, Yasuo Ohashi14. 1. Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan. Electronic address: iijima@med.kobe-u.ac.jp. 2. 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. 3. Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan. 4. 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. 5. Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan. 6. Department of Nephrology and Rheumatology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan. 7. Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan. 8. Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Shikata-cho, Okayama, Japan. 9. Department of Pediatrics, Wakayama Medical University, Wakayama, Japan. 10. Department of Pediatrics, Juntendo University Nerima Hospital, Nerima-ku, Tokyo, Japan. 11. Department of Pediatrics, Surugadai Nihon University Hospital, Chiyoda-ku, Tokyo, Japan. 12. Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, Suma-Ku, Kobe, Japan. 13. Department of Nephrology, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan. 14. Chuo University, Bunkyo-ku, Tokyo, Japan.
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. 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 givenrituximab 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.
RCT Entities:
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.