Effect of ramosetron in female patients with irritable bowel syndrome with diarrhea: a phase III long-term study
- 479 Downloads
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 (ClinicalTrials.gov ID: NCT01736423).
Keywords5-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
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.
- 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
- 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
- 14.World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. 64th WMA general assembly, Fortaleza, Brazil, October 2013. http://www.wma.net/en/30publications/10policies/b3/index.html. Accessed 20 Jan 2016.
- 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
- 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. http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4068B1_09_ICH-E1A-Guidelines.pdf. Accessed 20 Jan 2016.
- 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.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.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.
- 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