A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome

Kazuo Yoshioka, Yasuo Ohashi, Tadasu Sakai, Hiroshi Ito, Norishige Yoshikawa, Hajime Nakamura, Takakuni Tanizawa, Hiroyoshi Wada, Sunao Maki, J. Kadowaki, H. Tochimaru, S. Waga, T. Suzuki, Y. Kondou, H. Suzuki, S. Tomizawa, A. Matsui, K. Kanou, T. Nakahara, S. Akasi & 43 others H. Kurayama, H. Shiraga, S. Watanabe, Y. Suhara, S. Yoshida, M. Murakami, K. Yabuta, A. Takeda, M. Awazu, K. Ito, T. Kosaka, M. Honda, Y. Koitabashi, K. Iitaka, N. Kasai, Y. Yoshida, H. Nagasaka, M. Uchiyama, M. Hara, S. Tomizawa, S. Takahashi, T. Yazaki, K. Tsuzuki, A. Mizuno, S. Inaba, S. Tateishi, H. Kawakatsu, M. Tokuda, M. Kino, S. Matsuyama, H. Kamitsuji, Y. Seino, M. Taki, N. Takeda, H. Hayashibara, K. Okada, K. Hatae, Y. Ito, S. Hattori, M. Tuchiya, S. Yoshimitsu, S. Ito, M. Shimada

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Background: The use of corticosteroids or cytotoxic/immunosuppressive agents such as cyclophosphamide, chlorambucil, and cyclosporine for the treatment of frequently relapsing nephrotic syndrome (FRNS) is limited because of their adverse effects. This study was conducted to evaluate the efficacy and safety of mizoribine, a relatively new immunosuppressive drug developed in Japan, in children with FRNS. Methods: A double-blind, placebo- controlled, multicenter trial was carried out in children, from 2 to 19 years old, with FRNS. At relapse, patients were treated with prednisolone. According to a dynamic allocation, mizoribine or a placebo was concurrently administered to each patient. Prednisolone was gradually tapered and discontinued within 12 weeks. The test drug was maintained for 48 weeks. The primary end point was the relapse rate (the total number of relapses/the total treatment days for all patients). Analyses were performed according to the intention-to-treat principle. Results: The primary analysis was conducted on 99 mizoribine- and 98 placebo-treated patients. The relapse rate was lower in the mizoribine group than in the placebo group (0.0055 vs. 0.0067; ratio 0.81, 95% CI, 0.61 to 1.05, P = 0.12). The hazard ratio of the cumulative remission rate between the two groups was 0.79 (95% CI, 0.57 to 1.08). In the subgroups consisting of patients 10 years old or younger, the relapse rate ratio between the mizoribine subgroup (54 patients) and the placebo subgroup (57 patients) was 0.66 (95% CI, 0.44 to 0.94, P = 0.017). The hazard ratio of the cumulative remission rate between the two subgroups was 0.56 (95% CI, 0.37 to 0.85, P = 0.007). Hyperuricemia was the most common adverse event with mizoribine (16%), but was transient. Conclusions: Compared with the placebo, mizoribine significantly decreased the relapse rate and prolonged the remission period in the subgroup consisting of patients 10 years old or younger. This drug may be useful in young children with FRNS who generally relapse more frequently than older children.

Original languageEnglish
Pages (from-to)317-324
Number of pages8
JournalKidney International
Volume58
Issue number1
DOIs
Publication statusPublished - 2000
Externally publishedYes

Fingerprint

Nephrotic Syndrome
Multicenter Studies
Placebos
Recurrence
Immunosuppressive Agents
Prednisolone
Pharmaceutical Preparations
Chlorambucil
Hyperuricemia
bredinin
Cytotoxins
Double-Blind Method
Cyclophosphamide
Cyclosporine
Japan
Adrenal Cortex Hormones
Safety
Therapeutics

Keywords

  • Cytotoxicity
  • End-stage renal disease
  • Immunosuppression
  • Prednisolone
  • Steroid therapy

ASJC Scopus subject areas

  • Nephrology

Cite this

A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. / Yoshioka, Kazuo; Ohashi, Yasuo; Sakai, Tadasu; Ito, Hiroshi; Yoshikawa, Norishige; Nakamura, Hajime; Tanizawa, Takakuni; Wada, Hiroyoshi; Maki, Sunao; Kadowaki, J.; Tochimaru, H.; Waga, S.; Suzuki, T.; Kondou, Y.; Suzuki, H.; Tomizawa, S.; Matsui, A.; Kanou, K.; Nakahara, T.; Akasi, S.; Kurayama, H.; Shiraga, H.; Watanabe, S.; Suhara, Y.; Yoshida, S.; Murakami, M.; Yabuta, K.; Takeda, A.; Awazu, M.; Ito, K.; Kosaka, T.; Honda, M.; Koitabashi, Y.; Iitaka, K.; Kasai, N.; Yoshida, Y.; Nagasaka, H.; Uchiyama, M.; Hara, M.; Tomizawa, S.; Takahashi, S.; Yazaki, T.; Tsuzuki, K.; Mizuno, A.; Inaba, S.; Tateishi, S.; Kawakatsu, H.; Tokuda, M.; Kino, M.; Matsuyama, S.; Kamitsuji, H.; Seino, Y.; Taki, M.; Takeda, N.; Hayashibara, H.; Okada, K.; Hatae, K.; Ito, Y.; Hattori, S.; Tuchiya, M.; Yoshimitsu, S.; Ito, S.; Shimada, M.

In: Kidney International, Vol. 58, No. 1, 2000, p. 317-324.

Research output: Contribution to journalArticle

Yoshioka, K, Ohashi, Y, Sakai, T, Ito, H, Yoshikawa, N, Nakamura, H, Tanizawa, T, Wada, H, Maki, S, Kadowaki, J, Tochimaru, H, Waga, S, Suzuki, T, Kondou, Y, Suzuki, H, Tomizawa, S, Matsui, A, Kanou, K, Nakahara, T, Akasi, S, Kurayama, H, Shiraga, H, Watanabe, S, Suhara, Y, Yoshida, S, Murakami, M, Yabuta, K, Takeda, A, Awazu, M, Ito, K, Kosaka, T, Honda, M, Koitabashi, Y, Iitaka, K, Kasai, N, Yoshida, Y, Nagasaka, H, Uchiyama, M, Hara, M, Tomizawa, S, Takahashi, S, Yazaki, T, Tsuzuki, K, Mizuno, A, Inaba, S, Tateishi, S, Kawakatsu, H, Tokuda, M, Kino, M, Matsuyama, S, Kamitsuji, H, Seino, Y, Taki, M, Takeda, N, Hayashibara, H, Okada, K, Hatae, K, Ito, Y, Hattori, S, Tuchiya, M, Yoshimitsu, S, Ito, S & Shimada, M 2000, 'A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome', Kidney International, vol. 58, no. 1, pp. 317-324. https://doi.org/10.1046/j.1523-1755.2000.00168.x
Yoshioka, Kazuo ; Ohashi, Yasuo ; Sakai, Tadasu ; Ito, Hiroshi ; Yoshikawa, Norishige ; Nakamura, Hajime ; Tanizawa, Takakuni ; Wada, Hiroyoshi ; Maki, Sunao ; Kadowaki, J. ; Tochimaru, H. ; Waga, S. ; Suzuki, T. ; Kondou, Y. ; Suzuki, H. ; Tomizawa, S. ; Matsui, A. ; Kanou, K. ; Nakahara, T. ; Akasi, S. ; Kurayama, H. ; Shiraga, H. ; Watanabe, S. ; Suhara, Y. ; Yoshida, S. ; Murakami, M. ; Yabuta, K. ; Takeda, A. ; Awazu, M. ; Ito, K. ; Kosaka, T. ; Honda, M. ; Koitabashi, Y. ; Iitaka, K. ; Kasai, N. ; Yoshida, Y. ; Nagasaka, H. ; Uchiyama, M. ; Hara, M. ; Tomizawa, S. ; Takahashi, S. ; Yazaki, T. ; Tsuzuki, K. ; Mizuno, A. ; Inaba, S. ; Tateishi, S. ; Kawakatsu, H. ; Tokuda, M. ; Kino, M. ; Matsuyama, S. ; Kamitsuji, H. ; Seino, Y. ; Taki, M. ; Takeda, N. ; Hayashibara, H. ; Okada, K. ; Hatae, K. ; Ito, Y. ; Hattori, S. ; Tuchiya, M. ; Yoshimitsu, S. ; Ito, S. ; Shimada, M. / A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. In: Kidney International. 2000 ; Vol. 58, No. 1. pp. 317-324.
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title = "A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome",
abstract = "Background: The use of corticosteroids or cytotoxic/immunosuppressive agents such as cyclophosphamide, chlorambucil, and cyclosporine for the treatment of frequently relapsing nephrotic syndrome (FRNS) is limited because of their adverse effects. This study was conducted to evaluate the efficacy and safety of mizoribine, a relatively new immunosuppressive drug developed in Japan, in children with FRNS. Methods: A double-blind, placebo- controlled, multicenter trial was carried out in children, from 2 to 19 years old, with FRNS. At relapse, patients were treated with prednisolone. According to a dynamic allocation, mizoribine or a placebo was concurrently administered to each patient. Prednisolone was gradually tapered and discontinued within 12 weeks. The test drug was maintained for 48 weeks. The primary end point was the relapse rate (the total number of relapses/the total treatment days for all patients). Analyses were performed according to the intention-to-treat principle. Results: The primary analysis was conducted on 99 mizoribine- and 98 placebo-treated patients. The relapse rate was lower in the mizoribine group than in the placebo group (0.0055 vs. 0.0067; ratio 0.81, 95{\%} CI, 0.61 to 1.05, P = 0.12). The hazard ratio of the cumulative remission rate between the two groups was 0.79 (95{\%} CI, 0.57 to 1.08). In the subgroups consisting of patients 10 years old or younger, the relapse rate ratio between the mizoribine subgroup (54 patients) and the placebo subgroup (57 patients) was 0.66 (95{\%} CI, 0.44 to 0.94, P = 0.017). The hazard ratio of the cumulative remission rate between the two subgroups was 0.56 (95{\%} CI, 0.37 to 0.85, P = 0.007). Hyperuricemia was the most common adverse event with mizoribine (16{\%}), but was transient. Conclusions: Compared with the placebo, mizoribine significantly decreased the relapse rate and prolonged the remission period in the subgroup consisting of patients 10 years old or younger. This drug may be useful in young children with FRNS who generally relapse more frequently than older children.",
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author = "Kazuo Yoshioka and Yasuo Ohashi and Tadasu Sakai and Hiroshi Ito and Norishige Yoshikawa and Hajime Nakamura and Takakuni Tanizawa and Hiroyoshi Wada and Sunao Maki and J. Kadowaki and H. Tochimaru and S. Waga and T. Suzuki and Y. Kondou and H. Suzuki and S. Tomizawa and A. Matsui and K. Kanou and T. Nakahara and S. Akasi and H. Kurayama and H. Shiraga and S. Watanabe and Y. Suhara and S. Yoshida and M. Murakami and K. Yabuta and A. Takeda and M. Awazu and K. Ito and T. Kosaka and M. Honda and Y. Koitabashi and K. Iitaka and N. Kasai and Y. Yoshida and H. Nagasaka and M. Uchiyama and M. Hara and S. Tomizawa and S. Takahashi and T. Yazaki and K. Tsuzuki and A. Mizuno and S. Inaba and S. Tateishi and H. Kawakatsu and M. Tokuda and M. Kino and S. Matsuyama and H. Kamitsuji and Y. Seino and M. Taki and N. Takeda and H. Hayashibara and K. Okada and K. Hatae and Y. Ito and S. Hattori and M. Tuchiya and S. Yoshimitsu and S. Ito and M. Shimada",
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TY - JOUR

T1 - A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome

AU - Yoshioka, Kazuo

AU - Ohashi, Yasuo

AU - Sakai, Tadasu

AU - Ito, Hiroshi

AU - Yoshikawa, Norishige

AU - Nakamura, Hajime

AU - Tanizawa, Takakuni

AU - Wada, Hiroyoshi

AU - Maki, Sunao

AU - Kadowaki, J.

AU - Tochimaru, H.

AU - Waga, S.

AU - Suzuki, T.

AU - Kondou, Y.

AU - Suzuki, H.

AU - Tomizawa, S.

AU - Matsui, A.

AU - Kanou, K.

AU - Nakahara, T.

AU - Akasi, S.

AU - Kurayama, H.

AU - Shiraga, H.

AU - Watanabe, S.

AU - Suhara, Y.

AU - Yoshida, S.

AU - Murakami, M.

AU - Yabuta, K.

AU - Takeda, A.

AU - Awazu, M.

AU - Ito, K.

AU - Kosaka, T.

AU - Honda, M.

AU - Koitabashi, Y.

AU - Iitaka, K.

AU - Kasai, N.

AU - Yoshida, Y.

AU - Nagasaka, H.

AU - Uchiyama, M.

AU - Hara, M.

AU - Tomizawa, S.

AU - Takahashi, S.

AU - Yazaki, T.

AU - Tsuzuki, K.

AU - Mizuno, A.

AU - Inaba, S.

AU - Tateishi, S.

AU - Kawakatsu, H.

AU - Tokuda, M.

AU - Kino, M.

AU - Matsuyama, S.

AU - Kamitsuji, H.

AU - Seino, Y.

AU - Taki, M.

AU - Takeda, N.

AU - Hayashibara, H.

AU - Okada, K.

AU - Hatae, K.

AU - Ito, Y.

AU - Hattori, S.

AU - Tuchiya, M.

AU - Yoshimitsu, S.

AU - Ito, S.

AU - Shimada, M.

PY - 2000

Y1 - 2000

N2 - Background: The use of corticosteroids or cytotoxic/immunosuppressive agents such as cyclophosphamide, chlorambucil, and cyclosporine for the treatment of frequently relapsing nephrotic syndrome (FRNS) is limited because of their adverse effects. This study was conducted to evaluate the efficacy and safety of mizoribine, a relatively new immunosuppressive drug developed in Japan, in children with FRNS. Methods: A double-blind, placebo- controlled, multicenter trial was carried out in children, from 2 to 19 years old, with FRNS. At relapse, patients were treated with prednisolone. According to a dynamic allocation, mizoribine or a placebo was concurrently administered to each patient. Prednisolone was gradually tapered and discontinued within 12 weeks. The test drug was maintained for 48 weeks. The primary end point was the relapse rate (the total number of relapses/the total treatment days for all patients). Analyses were performed according to the intention-to-treat principle. Results: The primary analysis was conducted on 99 mizoribine- and 98 placebo-treated patients. The relapse rate was lower in the mizoribine group than in the placebo group (0.0055 vs. 0.0067; ratio 0.81, 95% CI, 0.61 to 1.05, P = 0.12). The hazard ratio of the cumulative remission rate between the two groups was 0.79 (95% CI, 0.57 to 1.08). In the subgroups consisting of patients 10 years old or younger, the relapse rate ratio between the mizoribine subgroup (54 patients) and the placebo subgroup (57 patients) was 0.66 (95% CI, 0.44 to 0.94, P = 0.017). The hazard ratio of the cumulative remission rate between the two subgroups was 0.56 (95% CI, 0.37 to 0.85, P = 0.007). Hyperuricemia was the most common adverse event with mizoribine (16%), but was transient. Conclusions: Compared with the placebo, mizoribine significantly decreased the relapse rate and prolonged the remission period in the subgroup consisting of patients 10 years old or younger. This drug may be useful in young children with FRNS who generally relapse more frequently than older children.

AB - Background: The use of corticosteroids or cytotoxic/immunosuppressive agents such as cyclophosphamide, chlorambucil, and cyclosporine for the treatment of frequently relapsing nephrotic syndrome (FRNS) is limited because of their adverse effects. This study was conducted to evaluate the efficacy and safety of mizoribine, a relatively new immunosuppressive drug developed in Japan, in children with FRNS. Methods: A double-blind, placebo- controlled, multicenter trial was carried out in children, from 2 to 19 years old, with FRNS. At relapse, patients were treated with prednisolone. According to a dynamic allocation, mizoribine or a placebo was concurrently administered to each patient. Prednisolone was gradually tapered and discontinued within 12 weeks. The test drug was maintained for 48 weeks. The primary end point was the relapse rate (the total number of relapses/the total treatment days for all patients). Analyses were performed according to the intention-to-treat principle. Results: The primary analysis was conducted on 99 mizoribine- and 98 placebo-treated patients. The relapse rate was lower in the mizoribine group than in the placebo group (0.0055 vs. 0.0067; ratio 0.81, 95% CI, 0.61 to 1.05, P = 0.12). The hazard ratio of the cumulative remission rate between the two groups was 0.79 (95% CI, 0.57 to 1.08). In the subgroups consisting of patients 10 years old or younger, the relapse rate ratio between the mizoribine subgroup (54 patients) and the placebo subgroup (57 patients) was 0.66 (95% CI, 0.44 to 0.94, P = 0.017). The hazard ratio of the cumulative remission rate between the two subgroups was 0.56 (95% CI, 0.37 to 0.85, P = 0.007). Hyperuricemia was the most common adverse event with mizoribine (16%), but was transient. Conclusions: Compared with the placebo, mizoribine significantly decreased the relapse rate and prolonged the remission period in the subgroup consisting of patients 10 years old or younger. This drug may be useful in young children with FRNS who generally relapse more frequently than older children.

KW - Cytotoxicity

KW - End-stage renal disease

KW - Immunosuppression

KW - Prednisolone

KW - Steroid therapy

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JF - Kidney International

SN - 0085-2538

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