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Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance: a prospective randomised clinical trial (DIAMOND2)

  • Original Article—Alimentary Tract
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Abstract

Background

The risk:benefit ratio of concomitant use of thiopurines with scheduled adalimumab (ADA) maintenance therapy for Crohn’s disease is controversial. The aim of this study is to identify the influence of withdrawal of thiopurines in patients in remission with combination therapy in an open-label, randomised, controlled trial (DIAMOND2; UMIN000009596).

Methods

Patients in corticosteroid-free clinical remission (CFCR) for ≥ 6 months with ADA (40 mg, s.c., every other week) scheduled maintenance combined with thiopurines were randomised into two groups, “continue” (Con) or “discontinue” (Dis) group of thiopurines, whereas all other patients kept receiving scheduled ADA maintenance therapy for 52 weeks. The primary endpoint was the proportion of patients in CFCR at week 52. Secondary endpoints were endoscopic remission (ER), trough levels of ADA in serum, and safety.

Results

Fifty patients were randomised to Con or Dis groups. Characteristics of patients were not significantly different between the groups. CFCR and ER prevalence at week 52 were not significantly different between groups (log rank, P = 0.704, P = 1.000, respectively). Trough levels of ADA were not significantly different between groups (P = 0.515). The proportion of patients with AAA positivity at week 52 was not significantly different (P = 0.437). ER at week 0 was involved in ER and triple remission at week 52. No serious adverse effects were observed in either group.

Conclusion

Continuation of thiopurines > 6 months offers no clear benefit over scheduled ADA monotherapy. CFCR, ER, and ADA trough level at week 52 were not significantly different between groups. ER at week 0 may be involved in better long-term clinical outcomes.

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Acknowledgements

We thank Arshad Makhdum, PhD, from Edanz Group (https://www.edanzediting.com/ac) for editing a draft of this manuscript. Members of the DIAMOND2 Study Group are: Katsuya Endo (Tohoku University), Motohiro Esaki (Kyushu University), Hiroyuki Hanai (Hamamatsu South Hospital), Taku Kobayashi and Toshifumi Hibi (Kitasato University Kitasato Institute Hospital), Sakiko Hiraoka (Okayama University), Tadakazu Hisamatsu (Kyorin University), Yutaka Honda (Niigata University), Satoko Inoue (Kobe City Medical Center General Hospital), Takuya Inoue (Osaka Medical College), Shuji Inoue (Kochi National Hospital), Tetsuya Ishida (Ishida Clinic of IBD and Gastroenterology), Hiroaki Ito (Kinshukai Infusion Clinic), Ryuichi Iwakiri (Saga University), Motoyoshi Izumi (Machida Municipal Hospital), Takashi Kagaya (Kanazawa University), Noriko Kamata (Osaka City University), Makoto Naganuma and Takanori Kanai (Keio University), Yumiko Naganawa, Hiroyuki Kaneto (Muroran City General Hospital), Kazuhito Kani and Shingo Kato (Saitama Medical University), Fukunori Kinjyo (Ryukyu University), Reiko Kunisaki (Yokohama City University Medical Center), Hiroki Yasaka and Koichi Kurahara (Matsuyama Red Cross Hospital), Lee Kyouwon (Moriguchikeijinkai Hospital), Yutaka Yano, Fumihito Hirai and Toshiyuki Matsui (Fukuoka University Chikushi Hospital), Takayuki Matsumoto (Iwate Medical University), Hiroki Tanaka and Satoshi Motoya (Sapporo Kosei General Hospital), Yoshinori Munemoto (Fukui-ken Saiseikai Hospital), Yuji Naito (Kyoto Prefectural University of Medicine), Tomoo Nakagawa (Chiba University), Yoko Yokoyama, Kenji Watanabe and Shiro Nakamura (Hyogo College of Medicine), Hiroshi Nakase (Sapporo Medical University, School of Medicine), Masanori Nojima (The University of Tokyo), Norimasa Fukata and Kazuichi Okazaki (Kansai Medical University), Sachiko Ouchi (Steel Memorial Hirohata Hospital), Hirotake Sakuraba (Hirosaki University), Masayuki Saruta (The Jikei University School of Medicine), Makoto Sasaki (Aichi Medical University), Takeshi Sugaya (Japan Red Cross Ashikaga Hospital), Yasuo Suzuki (Toho University Sakura Medical Center), Fuminao Takeshima (Nagasaki University), Hiroyuki Tamaki (Takamatsu Red Cross Hospital), Shinji Tanaka (Hiroshima University), Satoshi Tanida and Tsutomu Mizoshita (Nagoya City University), Keiichi Tominaga (Dokkyo Medical University), Masakazu Nagahori and Mamoru Watanabe (Tokyo Medical and Dental University), Masaki Yamashita (St. Marianna University School of Medicine), Atsushi Yoshida (Ofuna Central Hospital), and Naoki Yoshimura (Tokyo Yamate Medical Center).

Funding

Grant from the Ministry of Health, Labour and Welfare of Japan (“Investigation and research for intractable inflammatory bowel disease”).

Author information

Author notes

  1. Tadakazu Hisamatsu and Shingo Kato contributed equally to this work. All authors made substantial contributions to this work.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Third Department of Internal Medicine, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan

    Tadakazu Hisamatsu

  2. Department of Gastroenterology and Hepatology, Saitama Medical Centre, Saitama Medical University, Saitama, Japan

    Shingo Kato

  3. Inflammatory Bowel Disease Centre, Yokohama City University Medical Center, Kanagawa, Japan

    Reiko Kunisaki

  4. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Minoru Matsuura

  5. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan

    Masakazu Nagahori & Mamoru Watanabe

  6. Inflammatory Bowel Disease Center, Sapporo Kosei General Hospital, Sapporo, Japan

    Satoshi Motoya

  7. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Motohiro Esaki

  8. Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan

    Norimasa Fukata

  9. Departments of Gastroenterology, Kobe City Medical Center General Hospital, Hyogo, Japan

    Satoko Inoue

  10. Department of Internal Medicine, Japan Red Cross Ashikaga Hospital, Tochigi, Japan

    Takeshi Sugaya

  11. Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Hirotake Sakuraba

  12. Inflammatory Bowel Disease Center, Fukuoka University Chikushi Hospital, Chikushino, Japan

    Fumihito Hirai

  13. Division of Gastroenterology, Osaka City General Hospital, Osaka, Japan

    Kenji Watanabe

  14. Department of Intestinal Inflammation Research, Hyogo College of Medicine, Nishinomiya, Japan

    Kenji Watanabe

  15. Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan

    Takanori Kanai & Makoto Naganuma

  16. Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Hiroshi Nakase

  17. Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Japan

    Yasuo Suzuki

  18. Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan

    Toshifumi Hibi

  19. Center for Translational Research, Institute of Medical Science Hospital, University of Tokyo, Tokyo, Japan

    Masanori Nojima

  20. Division of Gastroenterology, Department of Medicine, Iwate Medical University, Morioka, Japan

    Takayuki Matsumoto

Authors
  1. Tadakazu Hisamatsu
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  2. Shingo Kato
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Consortia

DIAMOND2 Study Group

  • Katsuya Endo
  • , Motohiro Esaki
  • , Hiroyuki Hanai
  • , Taku Kobayashi
  • , Toshifumi Hibi
  • , Sakiko Hiraoka
  • , Tadakazu Hisamatsu
  • , Yutaka Honda
  • , Satoko Inoue
  • , Takuya Inoue
  • , Shuji Inoue
  • , Tetsuya Ishida
  • , Hiroaki Ito
  • , Ryuichi Iwakiri
  • , Motoyoshi Izumi
  • , Takashi Kagaya
  • , Noriko Kamata
  • , Makoto Naganuma
  • , Takanori Kanai
  • , Yumiko Naganawa
  • , Hiroyuki Kaneto
  • , Kazuhito Kani
  • , Shingo Kato
  • , Fukunori Kinjyo
  • , Reiko Kunisaki
  • , Hiroki Yasaka
  • , Koichi Kurahara
  • , Lee Kyouwon
  • , Yutaka Yano
  • , Fumihito Hirai
  • , Toshiyuki Matsui
  • , Takayuki Matsumoto
  • , Hiroki Tanaka
  • , Satoshi Motoya
  • , Yoshinori Munemoto
  • , Yuji Naito
  • , Tomoo Nakagawa
  • , Yoko Yokoyama
  • , Kenji Watanabe
  • , Shiro Nakamura
  • , Hiroshi Nakase
  • , Masanori Nojima
  • , Norimasa Fukata
  • , Kazuichi Okazaki
  • , Sachiko Ouchi
  • , Hirotake Sakuraba
  • , Masayuki Saruta
  • , Makoto Sasaki
  • , Takeshi Sugaya
  • , Yasuo Suzuki
  • , Fuminao Takeshima
  • , Hiroyuki Tamaki
  • , Shinji Tanaka
  • , Satoshi Tanida
  • , Tsutomu Mizoshita
  • , Keiichi Tominaga
  • , Masakazu Nagahori
  • , Mamoru Watanabe
  • , Masaki Yamashita
  • , Atsushi Yoshida
  •  & Naoki Yoshimura

Contributions

Concept and design of the study (TH, HN, KW, TM, YS, MW, TH), acquisition of data (SK, RK, MM, MN, SM, ME, NF, SI, TS, HS, FH, MN, TK), analyses and interpretation of data (TH, HN, KW, TM, MN), drafting of the manuscript (TH, HN, KW, TM, MN), critical revision of the manuscript for important intellectual content (YS, MW, TH), statistical analyses (MN) and study supervision (YS, MW, TH).

Corresponding author

Correspondence to Tadakazu Hisamatsu.

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Conflict of interest

T Hisamatsu: Honoraria: EA pharma Co. Ltd., AbbVie GK, Celgene K.K., Janssen Pharmaceutical K.K., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Mochida Pharmaceutical Co., Ltd., Nichi-lko Pharmaceutical Co., Ltd. Commercial research funding: EA pharma Co. Ltd., AbbVie GK, Daiichi-Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co., Ltd, Nippon Kayaku Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Mochida Pharmaceutical Co., Ltd., Astellas Pharma Inc., Asahi Kasei Medical Co., Ltd., ZERIA Pharmaceutical Co. Ltd. S. Kato: Honoraria: Mistubishi Tanabe Pharma Corporation, Janssenn Pharma K,K. R. Kunisaki: Honoraria: AbbVie GK, EA pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Nioppon Kayaku Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd., ZERIA Pharmaceutical Co. Ltd. Commercial research funding: AbbVie GK, EA pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., Mitsubishi Tanabe Pharma Corporation, RPM Co. Ltd, Takeda Pharmaceutical Co. Ltd. M. Matsuura: Honoraria: AbbVie GK, Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Nioppon Kayaku Co. Ltd., Kissei Pharmaceutical Co. Ltd. Commercial research funding: AbbVie GK, Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., Mochida Pharmaceutical Co., Ltd., Nioppon Kayaku Co. Ltd., JIMRO Co. M. Nagahori: Honoraria: Kissei Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co., Ltd., AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Nioppon Kayaku Co. Ltd., Asahi Kasei Medical Co., Ltd., ZERIA Pharmaceutical Co. Ltd., Astellas Pharma Inc., Nichi-lko Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. S. Motoya: Honoraria: Eisai Corporation, AbbVie GK, Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Corporation, Mochida Pharma Corporation, Janssen Pharmaceutical K.K. M. Esaki: Honoraria: AbbVie, Mitsubishi Tanabe Pharma Corporation. Commercial research funding: EA pharma Co. Ltd., AbbVie GK, Mitsubishi Tanabe Pharma Corporation. N. Fukata: no conflict of interest. S. Inoue: no conflict of interest. T. Sugaya: no conflict of interest. H. SAKURABA: Commercial research funding: Bristol-Myers Squibb, AbbVie GK, MSD Inc., Daiichi-Sankyo Co. Ltd., ZERIA Pharmaceutical Co. Ltd. F. Hirai: Honoraria: EA Pharma CO. Ltd, AbbVie GK, Mitsugishi Tanabe Pharma, Eisai CO.,Ltd. K. Watanabe: Honoraria: EA Pharma Co. Ltd., AbbVie, Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Mochida Pharmaceutical Co. Ltd., Janssen Pharmaceutical K.K, Takeda Pharmaceutical Co. Ltd. Commercial research funding: EA Pharma Co. Ltd., AbbVie, Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Astellas Pharma Inc. T. Kanai: Honoraria: EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., Yakult Honsha Co., Ltd., ZERIA Pharmaceutical Co. Ltd., Miyarisan Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co. Ltd. Commercial research funding: Eisai Corporation, JIMRO Co. Ltd., Nippon Kayaku Co. Ltd., Daiichi-Sankyo Co. Ltd., Tsumura & Co., Taiho Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., EN Otsuka Pharmaceutical Co. Ltd., Ezaki Glico Co. Ltd., RPM Co. Ltd., Yakult Bio-Science Foundation.M. Naganuma: Honoraria: EA Pharma Co. Ltd. Commercial research funding: EA Pharma Co. Ltd., ZERIA, Mochida Pharmaceutical CO. Ltd. H. Nakase: Honoraria: Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical CO. Ltd., Janssen Pharmaceutical K.K, AbbVie GK. Commercial research funding: Hoya group Pentax Medical. Boehringer Ingelheim GmbH, Daticho-Sankyo Co. Ltd. Y. Suzuki: Honoraria: AbbVie GK, Mitsubishi Tanabe Pharma Corporation, ZERIA Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., EA pharma Co. Ltd., Janssen Pharmaceutical K.K. Commercial research funding: AbbVie GK, Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., JIMRO Co. Ltd., Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., KISSEI. M. Watanabe: Honoraria: Mitsubishi Tanabe Pharma Corp., Eisai Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co. Ltd., AbbVie GK, Takeda Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., ZERIA Pharmaceutical Co. Ltd., Asahi Kasei Medical Co. Ltd., EA Pharma Co. Ltd., Astellas Pharma Inc., Mochida Pharmaceutical Co. Ltd., Janssen Pharmaceutical Co. Ltd., Gilead Sciences, Inc., Celgene Corp., Kissei Pharmaceutical Co. Ltd. Commercial research funding: Asahi Kasei Medical Co. Ltd., AbbVie GK, EA Pharma Co. Ltd., Eisai Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp., Otsuka Pharmaceutical Co. Ltd., Kyowa Hakko Kirin Co. Ltd., ZERIA Pharmaceutical Co. Ltd., JIMRO Co. Ltd., Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Mochida Pharmaceutical Co. Ltd., Daiichi-Sankyo Co. Ltd., Astellas Pharma Inc., MSD K.K., Dainippon Sumitomo Dainippon Pharma Co. Ltd., Bristol-Myers, K.K, Chugai Pharmaceutical Co. Ltd., Gilead Sciences Inc., Pfizer Inc., Miyarisan Pharmaceutical Co. Ltd., Kissei Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd. T. HIBI: Honoraria: Mitsubishi Tanabe Pharma CO., AbbVie GK, EA Pharma Co., Ltd. M. Nojima: no conflict of interest. T. Matsumoto: Honoraria: Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Janssen Pharmaceutical K.K. Commercial research funding: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., Nippon Kayaku Co. Ltd.

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The members of the group are listed in Acknowledgements.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1. Adverse effects (DOCX 15 kb)

Supplemental Figure 1. Design of the DIAMOND2 study (TIFF 55 kb)

Supplemental Figure 2. Flowchart of the DIAMOND2 study (TIFF 51 kb)

535_2019_1582_MOESM4_ESM.tif

Supplemental Figure 3. Proportion of patients with triple remission at week 52. Triple remission was defined as CFCR, endoscopic remission (SES-CD ≤2), and serological remission (CRP ≤0.10 mg/dl). Statistical analyses were by Welch’s t-test. Con: continue group; D: discontinue group. (TIFF 48 kb)

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Hisamatsu, T., Kato, S., Kunisaki, R. et al. Withdrawal of thiopurines in Crohn’s disease treated with scheduled adalimumab maintenance: a prospective randomised clinical trial (DIAMOND2). J Gastroenterol 54, 860–870 (2019). https://doi.org/10.1007/s00535-019-01582-w

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