Previous studies have indicated that ramosetron, a 5-hydroxytryptamine-3 receptor antagonist, achieves global improvement in irritable bowel syndrome (IBS) symptoms in male patients with IBS with diarrhea (IBS-D). However, in addition to global assessment it was deemed important to assess “clinically meaningful improvements, focusing on the patient’s chief complaint and the severity of major IBS symptoms”. We performed a randomized, placebo-controlled, phase IV pilot study to explore and examine efficacy variables that allow such evaluation of ramosetron in male patients with IBS-D.
We performed a prospective study of 115 male outpatients with IBS-D (according to the Rome III criteria), from June 2009 to December 2009 at 25 centers in Japan. After a one-week baseline period, subjects received either 5 μg of ramosetron (n = 47) or placebo (n = 51) once daily for 12 weeks. To evaluate “clinically meaningful improvements focusing on the severity of major IBS symptoms,” the Japanese version of the IBS severity index (IBSSI-J) was used.
Change in IBSSI-J overall score from baseline was −133.5 ± 110.72 in the ramosetron 5 μg group and −108.2 ± 94.44 in the placebo group (P = 0.228) at the last evaluation point. Differences in responder rates for at least a 50% reduction from baseline in IBSSI-J between the ramosetron 5 μg group and the placebo group were over 10%, except Month 1. The monthly responder rate for global assessment of relief of overall IBS symptoms in the ramosetron 5 μg group showed a statistically significant improvement compared to placebo at the second month (44.4% vs 18.4%, P = 0.012). The proportion of patients who had a ≥ 50% reduction in IBSSI-J overall score was 24/37 (64.9%) in the responder group on global assessment and 18/54 (33.3%) in the non-responder group at Week 12.
Further examination will be needed before IBSSI-J can be used in clinical trials of agents for IBS-D. However, this study revealed that response on global assessment was correlated with improvement in the IBSSI-J, suggesting that global assessment reflects improvement of the symptom severity of patients with IBS-D. (Clinicaltrials.gov ID: NCT00918411 Registered 9 June 2009).
Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006;130:1480–91. CrossRef
Miyata K, Ito H, Fukudo S. Involvement of the 5-HT 3 receptor in CRH-induced defecation in rats. Am J Physiol. 1998;274:G827–31. PubMed
Miyata K, Kamato T, Nishida A, Ito H, Katsuyama Y, Iwai 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. PubMed
Miyata K, Kamato T, Nishida A, Ito H, Yuki H, Yamano M, et al. Role of the serotonin 3 receptor in stress-induced defecation. J Pharmacol Exp Ther. 1992;261:297–303. PubMed
Matsueda K, Harasawa S, Hongo M, Hiwatashi N, Sasaki D. 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. CrossRefPubMed
Fukudo S, Matsueda K, Haruma K, Ida M, Hayase H, Akiho H, et al. Optimal dose of ramosetron in female patients with irritable bowel syndrome with diarrhea: a randomized, placebo-controlled phase II trial. Neurogastroenterol Motil. 2017. doi: 10.1111/nmo.13023.
Fukudo S, Kinoshita Y, Okumura T, Ida M, Hayashi K, Akiho H, et al. Effect of ramosetron in female patients with irritable bowel syndrome with diarrhea: a phase III long-term study. J Gastroenterol. 2016;9:874–82. CrossRef
Francis CY, Morris J, Whorwell PJ. The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther. 1997;11:396–402. CrossRef
Shinozaki M, Kanazawa M, Sagami Y, Endo Y, Hongo M, Drossman DA, et al. Validation of the Japanese version of the Rome II modulator questionnaire and irritable bowel syndrome severity index. J Gastroenterol. 2006;40:491–4. CrossRef
- Evaluation of the irritable bowel syndrome severity index in Japanese male patients with irritable bowel syndrome with diarrhea
- BioMed Central