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A randomized, placebo-controlled, double-blind clinical trial of rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: the G-PRIDE study

  • Original Article—Alimentary Tract
  • Published:
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Abstract

Background

The aim of this study was to investigate the efficacy of rikkunshito (RKT), a traditional Japanese medicine, combined with proton pump inhibitor (PPI) in patients with PPI-refractory non-erosive reflux disease (NERD).

Methods

Patients with PPI-refractory NERD (n = 242) were randomly assigned to the RKT group [rabeprazole (10 mg/day) + RKT (7.5 g/t.i.d.) for 8 weeks] or the placebo group (rabeprazole + placebo). After the 4- and 8-week treatments, we assessed symptoms and quality of life (QOL) using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG), Gastrointestinal Symptom Rating Scale (GSRS), and Short-Form Health Survey-8 (SF-8).

Results

There were no significant differences in FSSG and GSRS score improvement between these groups after the 4- and 8-week treatments. The mental component summary (MCS) scores of the SF-8 improved more in the RKT group (from 45.8 ± 8.1 to 48.5 ± 7.4) than in the placebo group (from 47.7 ± 7.1 to 48.4 ± 7.5) after the 4-week treatment (P < 0.05). The 8-week treatment with RKT was more effective for improvement of the degree of MCS score in patients with a low body mass index (<22) (P < 0.05) and significantly improved the acid-related dysmotility symptoms of FSSG in female and elderly patients (≥65 years).

Conclusion

There were no significant differences in improvement of GERD symptoms in patients with PPI-refractory NERD between these groups. However, RKT may be useful for improving mental QOL in non-obese patients and acid-related dyspeptic symptoms, especially in women and the elderly.

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Acknowledgments

We thank the site investigators and Sogo Rinsho Holdings Co., Ltd, Tokyo, Japan for their participation in the present study. We are grateful to the G-PRIDE study group as described below for their contribution to this study. The G-PRIDE study group: Katsuhiro Mabe, Hokkaido University Hospital; Mineo Kudo, Sapporo Hokuyu Hospital; Hiroko Oizumi, Hokuyukai Kaisei Hospital; Kazunori Eto, Shuichi Muto, Tomakomai City Hospital; Shinya Serikawa, Jyun Sakamoto, Sapporo Higashi Tokushukai Hospital; Kaku Hokari, Keiyukai Sapporo Hospital; Hiroaki Nema, Nikko Memorial Hospital; Satoru Kakizaki, Gunma University Hospital; Tomohiro Kudo, Takasaki General Medical Center, Hideyuki Suzuki, Kazuhiro Takahashi, Haramachi Red Cross Hospital; Daisuke Asaoka, Mariko Hojyo, Jyuntendo University School of Medicine; Kenji Nakamura, Kengo Tokunaga, Kyorin University School of Medicine; Tomoaki Matsumura, Chiba University Graduate School of Medicine; Kenichi Nakajima, Tako Central Hospital; Mitsushige Sugimoto, Takanori Yamada, Hamamatsu University School of Medicine; Yasuhiko Maruyama, Masanobu Kageoka, Fujieda Municipal General Hospital; Naohito Shirai, Enshu Hospital; Makoto Kodaira, Yaizu City General Hospital; Testuya Tanigawa, Osaka City University Guraduate School of Medicine; Natsuhiko Kameda, Hironori Uno, Ohno Memorial Hospital; Koichiro Nakagawa, Higashisumiyoshi Morimoto Hospital; Masahiro Ochi, Meijibashi Hospital; Kenjiro Otani, Ryuta Oiso, Nagayoshi General Hospital; Kiyoshi Ashida, Hirosi Yamashita, Osaka Saiseikai Nakatsu Hospital; Masahiro Sakaguchi, Moriguchi Keijinkai Hospital; Sanomura Makoto, Shinya Kaseda, Hokusetsu General Hopital, Seikeikai Hospital; Masahiro Shiraki, Shinsei Hospital; Osamu Saito, Rapport Aoyama Second Hospital; Takashi Kondo, Toshihiko Tomita, Jiro Watari, Hirokazu Fukui; Takashi Abe, Jyunsuke Oku, Takarazuka City Hospital; Mitsuhiko Kawaguchi, Kawaguchi Medical Clinic; Kyoichi Adachi, Shimane University Faculty of Medicine; Yoshinori Komazawa, Mika Yuki, Izumo City General Medical Center; Tomoo Fujisawa, Yoshinori Kushiyama, Erina Kakuta, Matsue Red Cross Hospital; Youichi Miyaoka, Yoshiya Morito, Shimane Prefectural Central Hospital; Koichiro Furuta, Masuda Medical Association Hospital; Yuichiro Eguchi, Shigetaka Kuroki, Eguchi Hospital; Seiji Tsunada, Ureshino Medical Center; Shinichi Ogata, Saga Prefectural Hospital Koseikan; Kohei Yamanouchi, Imari Arita Kyoritsu Hospital; Takahiro Noda, Nanae Tsuruoka, Karatsu Red Cross Hospital; Kiwamu Hasuda, Hattori Gastrointestinal Clinic; Yasushi Oda, Oda Gastrointestinal Clinic; Testuya Murao, Kumamoto Medical Center; Seiji Shiota, Oita University Faculty of Medicine; Hisanori Abe, Arita Gastrointestinal Hospital; Shigeaki Yasaka, Health Insurance Nankai Hospital; Fuminao Takeshima, Nagasaki University Graduate School of Biomedical Sciences.

Financial support for this study was provided by the Waksman Foundation of Japan INC., which has no commercial interest in RKT.

Conflict of interest

Some authors have received research grants, respectively: Mototsugu Kato from Otsuka Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd., AstraZeneca KK., Ltd., Astellas Pharma Inc., and Daiichi-Sankyo Co., Ltd.; Hiroshi Takeda from Tsumura & Co. Ltd., Eiji Umegaki from Takeda Pharmaceutical Co., Ltd.; Akihito Nagahara from Daiichi-Sankyo Co., Ltd.; Katsuhiko Iwakiri from Takeda Pharmaceutical Co.; Yoshikazu Kinoshita has served in speaking and teaching commitments for AstraZeneca KK, Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Eisai Co., Ltd., Taiho Pharmaceutical Co., Ltd., Daiichi-Sankyo, and MSD; ST from Eisai Co., Ltd.; Sumio Watanabe from AstraZeneca Inc., Eisai Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; Kazuhide Higuchi from AstraZeneca KK, Otsuka Pharmaceutical Co. Ltd., Eisai Co., Ltd., Daiichi-Sankyo Co. Ltd., and Nippon-Shinyaku Co. Ltd.; Motoyasu Kusano from Eisai Co., Ltd.; Kazuma Fujimoto from Eisai Co., Ltd., AstraZeneca KK., and Daiichi-Sankyo Co. Ltd.; Tetsuo Arakawa from Eisai Co., Ltd., Daiichi-Sankyo Co. Ltd., and Otsuka Pharmaceutical Co., Ltd. The Center for Clinical Research at Hamamatsu University School of Medicine has received grants from Takeda Pharmaceutical Co., Ltd., AstraZeneca KK, Eisai Co., Ltd., and Daiichi-Sankyo Co. Ltd., and Takahisa Furuta has received lecture fees from those companies. The Division of Upper Gastroenterology, Department of Internal Medicine at Hyogo College of Medicine has received grants from AstraZeneca KK, Astellas Pharma Inc., Otsuka Pharmaceutical Co. Ltd., Eisai Co., Ltd., Tsumura & Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., Yakult Co. Ltd., and Takeda Pharmaceutical Co., Ltd. The following people have nothing to declare: Kazunari Tominaga, Yasuyuki Shimoyama, Ryuichi Iwakiri, Kenji Furuta, Koichi Sakurai, Takeo Odaka, Hiroaki Kusunoki, Kazunari Murakami, and Ken Haruma.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan

    Kazunari Tominaga & Tetsuo Arakawa

  2. Division of Endoscopy, Hokkaido University Hospital, Sapporo, Japan

    Mototsugu Kato

  3. Department of Pathophysiology and Therapeutics, Hokkaido University Faculty of Pharmaceutical Sciences, Sapporo, Japan

    Hiroshi Takeda

  4. Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, Maebashi, Japan

    Yasuyuki Shimoyama & Motoyasu Kusano

  5. Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan

    Eiji Umegaki & Kazuhide Higuchi

  6. Department of Internal Medicine and Gastrointestinal Endoscopy, Saga Medical School, Saga, Japan

    Ryuichi Iwakiri

  7. Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Japan

    Kenji Furuta & Yoshikazu Kinoshita

  8. Department of Gastroenterology, Kumamoto University Graduate School of Medicine, Kumamoto, Japan

    Koichi Sakurai

  9. Department of Gastroenterology, Chiba University Graduate School of Medicine, Chiba, Japan

    Takeo Odaka

  10. Department of Gastroenterology, Kawasaki Medical School, Kurashiki, Japan

    Hiroaki Kusunoki & Ken Haruma

  11. Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan

    Akihito Nagahara & Sumio Watanabe

  12. Department of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan

    Katsuhiko Iwakiri

  13. Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Takahisa Furuta

  14. Department of Gastroenterology, Faculty of Medicine, Oita University, Yufu, Japan

    Kazunari Murakami

  15. Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan

    Hiroto Miwa

  16. The Third Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan

    Shin’ichi Takahashi

  17. Department of Internal Medicine, Saga Medical School, Saga, Japan

    Kazuma Fujimoto

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  1. Kazunari Tominaga
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  2. Mototsugu Kato
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  22. Kazuma Fujimoto
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  23. Tetsuo Arakawa
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G-PRIDE Study Group

Corresponding author

Correspondence to Tetsuo Arakawa.

Additional information

K. Tominaga, M. Kato, H. Takeda, Y. Shimoyama, E. Umegaki, and R. Iwakiri contributed equally to this work.

ClinicalTrials.gov, Number UMIN000005880.

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Tominaga, K., Kato, M., Takeda, H. et al. A randomized, placebo-controlled, double-blind clinical trial of rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: the G-PRIDE study. J Gastroenterol 49, 1392–1405 (2014). https://doi.org/10.1007/s00535-013-0896-9

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  • DOI: https://doi.org/10.1007/s00535-013-0896-9

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