Ramosetron Reduces Symptoms of Irritable Bowel Syndrome With Diarrhea and Improves Quality of Life in Women.

BACKGROUND & AIMS: Previous studies have indicated that serotonin-3-receptor antagonists might have a sex-specific effect in patients with irritable bowel syndrome with diarrhea (IBS-D). Alosetron has been approved for the treatment of only women, and ramosetron has been approved for the treatment for only men. We performed a randomized, placebo-controlled, phase 3 study to determine whether ramosetron reduces symptoms of IBS-D in women. METHODS: We performed a prospective study of 576 female outpatients with IBS-D (according to the Rome III criteria), from February 2013 through February 2014, at 70 academic Gastroenterology Departments in Japan. After a 1-week baseline period, subjects received either 2.5 µg ramosetron (n = 292) or placebo (n = 284) once daily for 12 weeks. Primary end points were the monthly rates of response for relief from overall IBS symptoms and increased stool consistency at the last evaluation point. Quality of life (QOL) also was quantified. RESULTS: A significantly higher proportion of patients given ramosetron reported global improvement (50.7%; 95% confidence interval [CI], 44.8-56.6) than patients given placebo (32.0%; 95% CI, 26.7-37.8)--a difference of 18.6% (95% CI, 10.7-26.5; P < .001). The relative risk was 1.58 (95% CI, 1.29-1.94) and the number needed to treat was 6 (95% CI, 4-10). A significantly higher proportion of patients in the ramosetron group reported increased stool consistency (40.8%; 95% CI, 35.1%-46.6%) than in the placebo group (24.3%; 95% CI, 19.4%-29.7%)--a difference of 16.5% (95% CI, 8.9%-24.0%; P < .001). Patients receiving ramosetron had significant reductions in abdominal pain and discomfort (P = .001) and greater improvement in QOL (P = .002) compared with placebo. Ramosetron induced constipation in 11.0% of patients. CONCLUSIONS: In a randomized, placebo-controlled study of 576 women with IBS-D, 2.5 µg ramosetron per day reduced symptoms and increased stool consistency and QOL. Clinicaltrials.gov no: NCT01870895.

The effect of fluvoxamine on the pharmacokinetics, safety, and tolerability of ramosetron in healthy subjects.

OBJECTIVE: To investigate the effects of multiple doses of fluvoxamine on the pharmacokinetics, safety, and tolerability of a single oral 10-mug dose of ramosetron. METHODS: This was a single-center, open, one-sequence cross-over study. On Day 1, healthy male and female subjects were administered a single dose of 10 mug ramosetron. Dosing of fluvoxamine started with an initial morning dose of 50 mg on Day 3, followed by a twice daily (12-h interval) dosing of 50 mg on Days 4-12. The morning dose on Day 11 was administered in combination with a single dose of 10 mug ramosetron. RESULTS: Co-administration of fluvoxamine with ramosetron resulted in an increase in the C(max) and AUC(0-inf) of ramosetron by 1.42-fold (90% CI 1.35-1.49) and 2.78-fold (90% CI 2.53-3.05), respectively. CONCLUSION: Co-administration of the CYP1A2 inhibitor fluvoxamine with ramosetron resulted in an interaction. However, the safety data collected during the study do not indicate that this interaction will cause any major safety concerns.

Evaluation of the irritable bowel syndrome severity index in Japanese male patients with irritable bowel syndrome with diarrhea.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).

Randomized, placebo-controlled, phase IV pilot study of ramosetron to evaluate the co-primary end points in male patients with irritable bowel syndrome with diarrhea.

BACKGROUND: Global assessment allows patients to assess improvement in multiple irritable bowel syndrome (IBS) symptoms. However, it was deemed important to assess "clinically meaningful improvements, focusing on the patient's chief complaint and the severity of major IBS symptoms" in addition to global assessment to show how ramosetron is effective for individual IBS symptoms. This is a pilot study to explore clinical endpoints focusing on the chief complaint of patients with IBS with diarrhea (IBS-D). METHODS: The same database was used in a previously reported post-marketing phase IV, randomized placebo-controlled pilot trial in male patients with IBS-D. The hypothesis is completely different from that of the other study. Patients with IBS-D diagnosed according to Rome III criteria were given either 5 µg of ramosetron (n = 47) or placebo (n = 51) once daily for 12 weeks after a one-week baseline period. To explore and examine endpoints that allow evaluation of "clinically meaningful improvements focusing on the patient's chief complaint," the chief complaint and its relief by this study drug were assessed in this exploratory study. RESULTS: Rates of patients with abdominal pain/discomfort, stool form and stool frequency which patients had as a chief complaint before administration were 34.0, 19.1 and 25.5%, respectively, in the ramosetron 5 µg group and 42.0, 18.0, and 20.0% in the placebo group. Responder rates for improvement in symptoms of the chief complaint that patients had before administration were 53.2% in the ramosetron 5 µg group and 42.0% in the placebo group at the last point. The greatest symptomatic improvement in the chief complaint in the ramosetron 5 µg group compared to the placebo group was shown with respect to stool consistency. Bristol Stool Form Scale (BSFS) scores were significantly lower in the ramosetron group than in the placebo group (4.36 ± 1.195 vs 4.85 ± 0.890 at the last point, P = 0.027) throughout the treatment period, except at week 6. CONCLUSIONS: Ramosetron acted most effectively on stool consistency. Improvement in stool consistency is considered to be a clinically meaningful endpoint in showing how ramosetron was effective for individual IBS symptoms. (Clinicaltrials.gov ID: NCT00918411. Registered 9 June 2009).

Cultural adaptation: translatability assessment and linguistic validation of the patient-reported outcome instrument for irritable bowel syndrome with diarrhea.

BACKGROUND AND OBJECTIVE: Following a 2009 US Food and Drug Administration guidance, a new patient-reported outcome (PRO) instrument was developed to support end points in multinational clinical trials assessing irritable bowel syndrome with diarrhea (IBS-D) symptom severity. Our objective was to assess the translatability of the IBS-D PRO instrument into ten languages, and subsequently perform a cultural adaptation/linguistic validation of the questionnaire into Japanese and US Spanish. MATERIALS AND METHODS: Translatability assessments of the US English version of the IBS-D PRO were performed by experienced PRO translators who were native speakers of each target language and currently residing in target-language countries. Languages were Chinese (People's Republic of China), Dutch (the Netherlands), French (Belgium), German (Germany), Japanese (Japan), Polish (Poland), Portuguese (Brazil), Russian (Russia), Spanish (Mexico), and Spanish (US). The project team assessed the instrument to identify potential linguistic and/or cultural adaptation issues. After the issues identified were resolved, the instrument was translated into Spanish (US) and Japanese through a process of two forward translations, one reconciled translation, and one backward translation. The project team reviewed the translated versions before the instruments were evaluated by cognitive debriefing interviews with samples of five Spanish (US) and five Japanese IBS-D patients. RESULTS: Linguistic and cultural adaptation concerns identified during the translatability assessment required minor revisions, mainly the presentation of dates/times and word structure. During the cognitive debriefing interviews, two of five Spanish respondents misunderstood the term "bowel movement" to mean only diarrhea in the Spanish version. Consequently, the term was changed from "movimiento intestinal" to "evacuaciones". None of the Japanese respondents identified issues with the Japanese version. CONCLUSION: The translatability of the IBS-D PRO instrument into ten target languages was confirmed, with only minor changes made to the translations of the instrument. The translation and linguistic validation into Spanish (US) and Japanese provide evidence that this instrument can be used in multinational trials and clinical settings.

The effect of paroxetine on the pharmacokinetics, safety, and tolerability of ramosetron in healthy subjects.

OBJECTIVE: The aim of our study was to investigate the effects of multiple doses of paroxetine on the pharmacokinetics, safety, and tolerability of a single oral 10-microg dose of ramosetron. METHODS This was an open, one-sequence crossover design study. On day 1, healthy male and female subjects were administered a single dose of 10 microg ramosetron. On the morning of day 3, the subjects were administered paroxetine to reach steady state, which consisted of morning doses of 20 mg on days 3-12. The dose on day 11 was administered in combination with a single dose of 10 microg ramosetron. RESULTS: In subjects genotyped as extensive CYP2D6 metabolizers, coadministration of paroxetine with ramosetron resulted in an increase in area under the curve from 0 to infinity (AUC(0-inf)) and the peak concentration (Cmax) of ramosetron by 1.14-fold (90% confidence interval (CI): 1.07-1.22) and by 1.06-fold (90% CI: 1.00-1.11), respectively. CONCLUSIONS: It can be concluded that the single-dose pharmacokinetic profile of ramosetron 10 microg is not affected to a clinically relevant degree by paroxetine 20 mg once daily administered for 10 days.