Journal of Gastroenterology

, Volume 51, Issue 9, pp 874–882 | Cite as

Effect of ramosetron in female patients with irritable bowel syndrome with diarrhea: a phase III long-term study

  • Shin FukudoEmail author
  • Yoshikazu Kinoshita
  • Toshikatsu Okumura
  • Motoko Ida
  • Kenta Hayashi
  • Hiraku Akiho
  • Yoshihiro Nakashima
  • Ken Haruma
Original Article—Alimentary Tract



The long-term safety of administration of ramosetron in female patients with irritable bowel syndrome with diarrhea (IBS-D) is unknown. The aim of this study was to assess the long-term safety, tolerability, and outcomes with the use of ramosetron in female patients with IBS-D.


This was a phase III, open-label, uncontrolled, long-term safety trial of the treatment of female Japanese patients with IBS-D, diagnosed according to the Rome III criteria. A total of 151 patients were given 2.5 μg of ramosetron for 4 weeks, and responders continued the same dose for another 48 weeks. Non-responders at 4 weeks were given 5 μg of ramosetron for 48 weeks. At the end of week 52, 106 patients receiving 2.5 μg and 17 patients receiving 5 μg had completed the study. Safety and efficacy including symptoms and quality of life (QOL) were evaluated.


Concerning safety, no serious adverse event related to ramosetron, specifically ischemic colitis, was observed in patients with either dose of ramosetron. However, constipation occurred in 19.7 % of patients given 2.5 μg and 10.5 % of patients given 5 μg of ramosetron. Ramosetron-treated patients showed high rates of global improvement. Stool consistency, abdominal pain and discomfort, and IBS-QOL were also improved at the last evaluation point.


The results provide evidence of the long-term safety and efficacy of treatment with 2.5 and 5 μg of ramosetron in female patients with IBS-D. Clinicians should be aware that one-fifth of women with IBS-D receiving ramosetron may suffer from constipation during treatment ( ID: NCT01736423).


5-Hydroxytryptamine Abdominal pain Abdominal discomfort Global improvement 



Bristol Stool Form Scale

95 % CI

95 % confidence interval


Food and Drug Administration


Health-related quality of life




5-Hydroxytryptamine 3 receptor


Irritable bowel syndrome


Irritable bowel syndrome with constipation


Irritable bowel syndrome with diarrhea


Mixed irritable bowel syndrome


Unsubtyped irritable bowel syndrome


Irritable bowel syndrome-quality of life


Minimum clinically important difference


Number needed to treat


Relative risk


Standard deviation



The authors would like to thank the following investigators for participating in the study: Haruhiro Ankoh, Tetsu Aoki, Takehiro Arai, Masae Banno, Shin Fukui, Tomoaki Hatakeyama, Hitoshi Hongo, Atsushi Isono, Tohoru Isono, Yoshifumi Jinnouchi, Shigeyasu Kamata, Hitoshi Kaneko, Toru Kanematsu, Daijo Kasahara, Hiroyuki Kimura, Toshio Komazaki, Tatsumi Koshiyama, Osamu Kunihiro, Hidenori Kurakata, Yoshio Matsuda, Kiichi Matsuyama, Ikuo Mitani, Shinichi Miyazaki, Koji Mori, Kouetsu Morita, Sanai Noguchi, Hiroshi Nozawa, Hirozumi Obata, Toshiaki Ochiai, Toshihide Ohmori, Tetsuo Ohshima, Teruki Oki, Tetsuya Sanji, Koichi Sato, Koji Sawada, Shigeru Shirota, Tomohiro Tada, Masahiro Takada, Hiroyuki Takahashi, Hirohisa Tanimura, Toshiaki Terada, Satoki Tokito, Osamu Ueda, Yoshiya Umemoto, Nobutoshi Watanabe, Asako Yamada, Norimichi Yamada, and Tadashi Yokoyama. The authors would also like to thank the following investigators for assisting with the study: Akito Nishida, Mayumi Yamano, Hisatake Hayase, and Michie Yagi. Statistical analysis of the entire data set pertaining to efficacy (specifically, the primary and secondary efficacy endpoints) and safety (specifically, serious adverse events as defined in the Japanese guidelines) was performed in accordance with the standard procedures of Astellas Pharma Inc.

Compliance with ethical standards

Conflict of interest

Shin Fukudo, Yoshikazu Kinoshita, Toshikatsu Okumura, and Ken Haruma are medical consultants under contract with Astellas Pharma Inc.; Motoko Ida, Kenta Hayashi, Hikaru Akiho, and Yoshihiro Nakashima are employees of Astellas Pharma Inc.


This research was funded by Astellas Pharma Inc., Tokyo, Japan.


  1. 1.
    Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006;130:1377–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Fukudo S, Kaneko H, Akiho H, et al. Evidence-based clinical practice guidelines for irritable bowel syndrome. J Gastroenterol. 2015;50:11–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Fukudo S, Hahm KB, Zhu Q, et al. Survey of clinical practice for irritable bowel syndrome in East Asian countries. Digestion. 2015;91:99–109.PubMedGoogle Scholar
  4. 4.
    Mawe GM, Coates MD, Moses PL. Review article: intestinal serotonin signaling in irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1067–76.CrossRefPubMedGoogle Scholar
  5. 5.
    Hassaine G, Deluz C, Grasso L, et al. X-ray structure of the mouse serotonin 5-HT3 receptor. Nature. 2014;512:276–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Andresen V, Montori VM, Keller J, et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2008;6:545–55.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Friedel D, Thomas R, Fisher RS. Ischemic colitis during treatment with alosetron. Gastroenterology. 2001;120:557–60.CrossRefPubMedGoogle Scholar
  8. 8.
    Camilleri M, Northcutt AR, Kong S, et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet. 2000;355:1035–40.CrossRefPubMedGoogle Scholar
  9. 9.
    Matsueda K, Harasawa S, Hongo M, et al. A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea-predominant irritable bowel syndrome. Digestion. 2008;77:225–35.CrossRefPubMedGoogle Scholar
  10. 10.
    Matsueda K, Harasawa S, Hongo M, et al. A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome. Scand J Gastroenterol. 2008;43:1202–11.CrossRefPubMedGoogle Scholar
  11. 11.
    Fukudo S, Ida M, Akiho H, et al. Effect of ramosetron on stool consistency in male patients with irritable bowel syndrome with diarrhea. Clin Gastroenterol Hepatol. 2014;12(953–959):e4.PubMedGoogle Scholar
  12. 12.
    Lee KJ, Kim NY, Kwon JK, et al. Efficacy of ramosetron in the treatment of male patients with irritable bowel syndrome with diarrhea: a multicenter, randomized clinical trial, compared with mebeverine. Neurogastroenterol Motil. 2011;23:1098–104.CrossRefPubMedGoogle Scholar
  13. 13.
    Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480–91.CrossRefPubMedGoogle Scholar
  14. 14.
    World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. 64th WMA general assembly, Fortaleza, Brazil, October 2013. Accessed 20 Jan 2016.
  15. 15.
    Heaton KW, Ghosh S, Braddon FE. How bad are the symptoms and bowel dysfunction of patients with the irritable bowel syndrome? A prospective, controlled study with emphasis on stool form. Gut. 1991;32:73–9.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chey WD, Chey WY, Heath AT, et al. Long-term safety and efficacy of alosetron in women with severe diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. 2004;99:2195–203.CrossRefPubMedGoogle Scholar
  17. 17.
    Fukudo S, Hongo M, Kaneko H, Takano M, Ueno R. Lubiprostone increases spontaneous bowel movement frequency and quality of life in patients with chronic idiopathic constipation. Clin Gastroenterol Hepatol. 2015;13(294–301):e5.PubMedGoogle Scholar
  18. 18.
    Miyata K, Kamato T, Nishida A, et al. Pharmacologic profile of (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (YM060), a potent and selective 5-hydroxytryptamine3 receptor antagonist, and its enantiomer in the isolated tissue. J Pharmacol Exp Ther. 1991;259:15–21.PubMedGoogle Scholar
  19. 19.
    Miyata K, Kamato T, Nishida A, et al. Role of the serotonin3 receptor in stress-induced defecation. J Pharmacol Exp Ther. 1992;261:297–303.PubMedGoogle Scholar
  20. 20.
    Miyata K, Ito H, Fukudo S. Involvement of the 5-HT3 receptor in CRH-induced defecation in rats. Am J Physiol. 1998;274:G827–31.PubMedGoogle Scholar
  21. 21.
    Patrick DL, Drossman DA, Frederick IO, et al. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998;43:400–11.CrossRefPubMedGoogle Scholar
  22. 22.
    Kanazawa M, Drossman DA, Shinozaki M, et al. Translation and validation of a Japanese version of the irritable bowel syndrome-quality of life measure (IBS-QOL-J). Biopsychosoc Med. 2007;1:6.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    International conference on harmonisation: Guideline for industry. The extent of population exposure to assess clinical safety: for drugs intended for long-term treatment of non-life-threatening conditions. E1; 1995. pp. 1–4. Accessed 20 Jan 2016.
  24. 24.
    Ohta M, Suzuki T, Furuya T, et al. Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. III. Pharmacological evaluations and molecular modeling studies of optically active 4,5,6,7-tetrahydro-1H-benzimidazole derivatives. Chem Pharm Bull (Tokyo). 1996;44:1707–16.CrossRefGoogle Scholar
  25. 25.
    Hirata T, Keto Y, Nakata M, et al. Effects of serotonin 5-HT3 receptor antagonists on stress-induced colonic hyperalgesia and diarrhoea in rats: a comparative study with opioid receptor agonists, a muscarinic receptor antagonist and a synthetic polymer. Neurogastroenterol Motil. 2008;20:557–65.CrossRefPubMedGoogle Scholar
  26. 26.
    Fukudo S, Matsueda K, Haruma K, et al. Optimal dose of ramosetron in female patients with irritable bowel syndrome with diarrhea: a randomized, placebo-controlled phase II trial. Gastroenterology 2015;148(Suppl 1):S-659.Google Scholar
  27. 27.
    Fukudo S, Kinoshita Y, Okumura T, et al. Ramosetron reduces symptoms of irritable bowel syndrome with diarrhea and improves quality of life in women. Gastroenterology. 2015. doi: 10.1053/j.gastro.2015.10.047.
  28. 28.
    Drossman DA, Morris CB, Hu Y, et al. Characterization of health related quality of life (HRQOL) for patients with functional bowel disorder (FBD) and its response to treatment. Am J Gastroenterol. 2007;102:1442–53.CrossRefPubMedGoogle Scholar
  29. 29.
    Grover M, Camilleri M. Ramosetron in irritable bowel syndrome with diarrhea: new hope or the same old story? Clin Gastroenterol Hepatol. 2014;12:960–2.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Chiba T, Yamamoto K, Sato S, Suzuki K. Long-term efficacy and safety of ramosetron in the treatment of diarrhea-predominant irritable bowel syndrome. Clin Exp Gastroenterol. 2013;6:123–8.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kux L. Department of Health and Human Services, Food and Drug Administration [docket no. FDA–2012–D–0146]: guidance for industry on irritable bowel syndrome—clinical evaluation of drugs for treatment: availability. Fed Reg. 2012;77:32124–5.Google Scholar

Copyright information

© Japanese Society of Gastroenterology 2016

Authors and Affiliations

  • Shin Fukudo
    • 1
    Email author
  • Yoshikazu Kinoshita
    • 2
  • Toshikatsu Okumura
    • 3
  • Motoko Ida
    • 4
  • Kenta Hayashi
    • 5
  • Hiraku Akiho
    • 5
  • Yoshihiro Nakashima
    • 6
  • Ken Haruma
    • 7
  1. 1.Department of Behavioral MedicineTohoku University Graduate School of MedicineSendaiJapan
  2. 2.Department of Gastroenterology, Faculty of MedicineShimane UniversityIzumoJapan
  3. 3.Department of General MedicineAsahikawa Medical UniversityAsahikawaJapan
  4. 4.Development Planning and AdministrationAstellas Pharma Inc.TokyoJapan
  5. 5.Japan/Asia Clinical Development 2Astellas Pharma Inc.TokyoJapan
  6. 6.Data ScienceAstellas Pharma Inc.TokyoJapan
  7. 7.Department of GastroenterologyKawasaki Medical SchoolKurashikiJapan

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