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Study protocol: mycophenolate mofetil as maintenance therapy after rituximab treatment for childhood-onset, complicated, frequently-relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicenter double-blind, randomized, placebo-controlled trial (JSKDC07)

Authors
  • Horinouchi, Tomoko1
  • Sako, Mayumi2
  • Nakanishi, Koichi3
  • Ishikura, Kenji4
  • Ito, Shuichi5
  • Nakamura, Hidefumi6
  • Oba, Mari Saito7
  • Nozu, Kandai1
  • Iijima, Kazumoto1
  • 1 Kobe University Graduate School of Medicine, Department of Pediatrics, 5-1 Kusunoki-cho 7 chome, Chuo-ku, Kobe, 650-0017, Japan , Kobe (Japan)
  • 2 National Center for Child Health and Development, Division for Clinical Trials, Department of Clinical Research Promotion, Clinical Research Center, Tokyo, Japan , Tokyo (Japan)
  • 3 University of the Ryukyus, Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, Okinawa, Japan , Okinawa (Japan)
  • 4 National Center for Child Health and Development, Division of Nephrology and Rheumatology, Tokyo, Japan , Tokyo (Japan)
  • 5 Yokohama City University, Department of Pediatrics, Graduate School of Medicine, Yokohama, Japan , Yokohama (Japan)
  • 6 National Center for Child Health and Development, Clinical Research Center, Tokyo, Japan , Tokyo (Japan)
  • 7 Toho University, Department of Medical Statistics, Tokyo, Japan , Tokyo (Japan)
Type
Published Article
Journal
BMC Nephrology
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Nov 01, 2018
Volume
19
Issue
1
Identifiers
DOI: 10.1186/s12882-018-1099-7
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundIdiopathic nephrotic syndrome (INS) is the most common chronic glomerular disease in children. Approximately 80–90% of patients with childhood INS have steroid-sensitive nephrotic syndrome (SSNS), and can obtain remission with steroid therapy, while the remainder have steroid-resistant nephrotic syndrome (SRNS). Furthermore, approximately 50% of children with SSNS develop frequently-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). Children with FRNS/SDNS are usually treated with immunosuppressive agents such as cyclosporine, cyclophosphamide, or mizoribine in Japan. However, 10–20% of children receiving immunosuppressive agents still show frequent relapse and/or steroid dependence during or after treatment, which is defined as complicated FRNS/SDNS. Furthermore, 30% of SRNS patients who obtain remission after additional treatments such as cyclosporine also turn out to be complicated FRNS/SDNS. For such complicated FRNS/SDNS patients, rituximab (RTX) is currently used; however, recurrence after RTX treatment also remains an open issue. Because long-term use of existing immunosuppressive drugs has limitations, development of a novel treatment for maintenance therapy after RTX is desirable. Mycophenolate mofetil (MMF) is an immunosuppressive drug with fewer side effects than cyclosporine or cyclophosphamide. Importantly, recent studies have reported the efficacy of MMF in children with nephrotic syndrome.MethodsWe conduct a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of MMF after RTX therapy in children with complicated FRNS/SDNS. Patients are allocated to either RTX plus MMF treatment group, or RTX plus placebo treatment group. For the former group, MMF is administered at a dose of 1000–1200 mg/m2/day (maximum 2 g/day) twice daily for 17 months after RTX treatment. The primary endpoint is time-to-treatment failure (development of frequent relapses, steroid dependence or steroid resistance).DiscussionThe results will provide important data on the use of MMF as maintenance therapy after RTX to prevent complicated FRNS/SDNS patients from declining into treatment failure. In future, MMF in conjunction with RTX treatment may permit increased duration of remission in ‘complicated’ FRNS/SDNS cases.Trial registrationThis trial was prospectively registered to UMIN Clinical Trials Registry on June 23, 2014 (UMIN Trial ID: UMIN000014347).

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