Efficacy of Ramosetron in the Treatment of Male Patients with Irritable Bowel

Neurogastroenterol Motil (2011) 23, 1098–e540 doi: 10.1111/j.1365-2982.2011.01771.x

Efﬁcacy of ramosetron in the treatment of male patients with irritable bowel syndrome with diarrhea: a multicenter, randomized clinical trial, compared with mebeverine

K. J. LEE,* N. Y. KIM, J. K. KWON,à K. C. HUH,§ O. Y. LEE,– J. S. LEE,** S. C. CHOI, C. I. SOHN,àà S. J. MYUNG,§§ H. J. PARK,–– M. K. CHOI,*** Y. T. BAK & P. L. RHEEàà

*Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea àDepartment of Internal Medicine, Daeku Catholic University College of Medicine, Daeku, Korea §Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea –Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea **Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul, Korea Department of Internal Medicine, Wonkwang University College of Medicine, Iksan, Korea ààDepartment of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea §§Department of Internal Medicine, Ulsan University College of Medicine, Ulsan, Korea ––Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea ***Department of Internal Medicine, Catholic University College of Medicine, Seoul, Korea Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea

Abstract secondary endpoints were changes in each symptom

Background The 5-HT3 receptor antagonists are score and the safety profiles. Key Results The known to be effective for the treatment of diarrhea- responder rates for global IBS symptoms, abdominal predominant irritable bowel syndrome (IBS), but not pain/discomfort and abnormal bowel habits in the widely used yet. The aim of this study was to ramosetron and mebeverine groups significantly compare the efficacy and safety of ramosetron, increased during the treatment period. The severity a 5-HT3 receptor antagonist, and mebeverine in scores of abdominal pain/discomfort and urgency, male patients with IBS with diarrhea (IBS-D). the stool form score, and the stool frequency in both Methods This study was performed in a multicenter, treatment arms were significantly reduced, compared randomized, open-label design. Data of 343 male with the baselines. There were no significant differ- patients with IBS-D who were randomized to either ences in the responder rates (37% vs 38% on a 4-week treatment of ramosetron 5 lg once daily or ITT analysis) and adverse event profiles between the a 4-week treatment of mebeverine 135 mg three ramosetron and mebeverine groups. Neither severe times daily were analyzed by the intent-to-treat constipation nor ischemic colitis was reported analysis. The primary efficacy parameter was the by ramosetron-treated patients. Conclusions & proportion of patients with adequate relief of IBS Inferences Ramosetron 5 lg once daily is as effective symptoms at the last week of treatment. The as mebeverine three times daily in male patients with IBS-D. Address for Correspondence Keywords 5-HT3 receptor antagonist, irritable bowel Poong-Lyul Rhee, Department of Medicine, Samsung Medical syndrome, mebeverine, ramosetron, Rome III criteria. Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Korea. Abbreviations: C-IBS, constipation-predominant irritable Tel: +82 2 3410 3409; fax: +82 2 3410 6983; bowel syndrome; D-IBS, diarrhea-predominant irritable e-mail: [email protected] Received: 15 May 2011 bowel syndrome; 5-HT, 5-Hydroxytrytamine; IBS, irritable Accepted for publication: 27 July 2011 bowel syndrome; IBS-C, irritable bowel syndrome with

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constipation; IBS-D, irritable bowel syndrome with IBS patients has demonstrated that alosetron is signif- diarrhea. icantly more effective than mebeverine in improving symptoms.13 As alosetron is not available in South Korea, direct comparison of efficacy between ramose- INTRODUCTION tron and alosetron is not feasible. Thus, we conducted a Irritable bowel syndrome (IBS) is a common gastroin- double-blind, randomized trial to compare the efficacy testinal disorder characterized by abdominal pain or and safety of ramosetron and mebeverine in male discomfort and alterations in bowel habits without patients with IBS-D meeting the Rome III criteria. structural and biochemical abnormalities.1 Studies Through this trial, we might be able to compare the have reported a worldwide prevalence of 10–20%.2–4 efficacy and tolerability of ramosetron and alosetron The research on IBS pathophysiology is of importance, indirectly. As studies comparing ramosetron with largely because of the possibility of developing targeted placebo in patients with D-IBS have been already therapies. As medical treatment for many patients reported,11,12 we did not include a placebo group in with IBS remains unsatisfactory, development of more the present study to simplify the study protocol and effective drugs is required. reduce the study period as well as the number of

The 5-Hydroxytrytamine (5-HT) acts on the 5-HT3 subjects needed in the study. receptors on parasympathetic ganglia to cause smooth muscle contraction and an increase in intestinal PATIENTS AND METHODS secretion by stimulating acetylcholine release from nerve terminals. Alosetron, a 5-HT receptor antago- 3 Patients nist, has been reported to be effective in the treatment of female patients with D-IBS.5–7 However, because of This was a multicenter (23 centers), randomized, open-label, serious gastrointestinal events reported in IBS patients parallel-group, non-inferiority comparative study conducted in South Korea from January 2010 to December 2010. The study treated with alosetron, it is available only in the USA protocol was approved by the institutional review board of each with a limited access program for women with severe study center and conducted in accordance with the ethical D-IBS refractory to conventional therapy. principles based on the Declaration of Helsinki and good clinical Ramosetron hydrochloride (Ramosetron), a tetra- practice. Written, informed consent was obtained from all patients before they entered the study. hydrobenzimidazole derivative, is a potent and selective Male patients aged 18–64 years with a diagnosis of IBS-D 5-HT3 receptor antagonist. Originally, ramosetron has meeting the Rome III diagnostic criteria were invited to partic- been used for antiemetic therapy in cancer patients, and ipate in this study. We confirmed the symptoms by interviewing the patient. Organic diseases were ruled out by a sigmoidoscopic for the prevention of postoperative nausea and vomiting. examination or barium enema in patients <49 years of age and by Ramosetron dose-dependently suppresses defecation colonoscopic examination or barium enema in patients >50 years disturbance induced by corticotrophin-releasing hor- of age, performed after the appearance of symptoms and within mone.8 Ramosetron has long-lasting inhibitory effects the last 5 years. Before randomization, a week of basal evaluation for the confirmation of bowel habits and sufficient fre- on stress-induced defecation disturbance in rats, but quency of abdominal pain/discomfort was performed. Eligible 9 does not influence normal defecation. Unlike existing patients were those who experienced abdominal pain/discomfort antidiarrheal and spasmolytic agents, 5-HT3 receptor at least 2 days a week during basal evaluation. Severity of antagonists have inhibitory effects on colonic nocicep- abdominal pain/discomfort was assessed on a 5-point scale 10 (0: none, 1: mild, 2: moderate, 3: severe, 4: intolerable). Stool tion. These findings suggest that ramosetron has form was evaluated by the Bristol stool form scale (1: separate potential as a useful therapeutic agent for IBS with hard lumps like nuts, 2: sausage-shaped but lumpy, 3: like a diarrhea (IBS-D). Until now, only two clinical trials of sausage but with cracks on its surface, 4: like a sausage or snake, ramosetron for the treatment of patients with D-IBS smooth and soft, 5: soft blots with clear-cut edges, 6: fluffy 11,12 pieces with ragged edges, a mushy stool, 7: watery, no solid have been reported in the literature. Studies show pieces, entirely liquid). During the 1-week basal period, the that the administration of ramosetron 5 lg once daily severity of abdominal pain/discomfort and urgency, stool con- has beneficial effects on IBS symptoms of male patients sistency, and stool frequency were checked daily to confirm that with D-IBS, compared with placebo. patients had suitable symptoms. When there was no stool, a value of 0 was assigned. Patients whose stool form was not type Various types of smooth muscle relaxants and 6 or 7 and whose stool frequency was <3 times per week during antispasmodics have been used in an attempt to the 1-week basal period were excluded from the enrollment. ameliorate IBS symptoms. Mebeverine is an antispas- Patients were excluded if they had a history of a surgical resection of the stomach, or intestine (excluding appendicitis or modic agent that has been commonly prescribed for the resection of benign polyps), if they had a history of inflammatory treatment of D-IBS in many countries. A double-blind, bowel disease, ischemic colitis or malignant tumors, if they had randomized trial comparing the efficacy and tolerability complications from infectious enteritis, hyperthyroidism or of alosetron and mebeverine in female non-constipated hypothyroidism, if they used drugs potentially affecting the

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efficacy of the study-drug (patients who could undergo a washout period of ‡3 days before the start of the run-in period were Statistical analysis acceptable), if they had a history of drug or alcohol abuse within The sample size was calculated, based on 90% power at a = 0.05. the past year or were currently abusing them, if they had severe The responder rate at week 4 was assumed to be 30% for depression or an anxiety disorder potentially affecting the mebeverine14 and 35% for ramosetron.13 With this assumption, efficacy of the study-drug, if they had complications from a the number of patients per treatment group needed to document serious cardiovascular disease, respiratory disease, renal disease, non-inferiority of the ramosetron treatment in the proportion of hepatic disease, gastrointestinal disease (excluding IBS), hemato- patients with adequate relief compared with the mebeverine logical disease, neurological disease, or psychiatric disease, or if treatment was 167 in each arm. A total of 350 patients (175 they were allergic to drugs. Patients who were regarded by the patients per group) was planned to be randomized in the study, study investigators as not being suitable participants were also allowing for a 5% dropout rate. The primary efficacy analysis was excluded. based on the intent-to-treat (ITT) population, which consisted of all randomized patients who received at least one dose of study medication and had at least one postbaseline efficacy measure- Randomization and treatment ment. All efficacy analyses were also conducted in the per- Following the screening and 1-week basal periods, enrolled protocol (PP) population, which included all patients within the patients were randomized to one of two study arms. The ITT population who took more than 50% of their assigned drugs patients were given either ramosetron (Irribow; Astellas Pharma and had no major protocol violations. The change of weekly Korea Inc., Seoul, South Korea) 5 lg once daily taken before responder rates during the study period was evaluated by 4-sample breakfast for 4 weeks or mebeveine (Duspatalin; JW Pharmaceu- test for equality of proportions without continuity correction with ticals, Seoul, South Korea) 135 mg three times daily taken before R 2.10.1. The responder rates between the ramosetron and meals for 4 weeks. Treatment assignments were carried out by a mebeverine treatment groups were compared by the chi-square computer-generated randomization schedule that was designed test. The change of each symptom score from baseline at each to allocate patients among the two treatment arms in a 1:1 ratio. time point was analyzed using repeated measures ANOVA model This is an open-label study and the tablets of ramosetron were (Time effect of RMANOVA). The P value of 0.05 was considered to be not identical to the mebeverine tablets. The medications statistically significant. If more than two daily scores were affecting gastrointestinal motility, sensation, or stool form were missing during any week of treatment, the average score for that not permitted. Follow-up visits during the study period were week was defined as missing. Statistical analyses were performed scheduled at weeks 2 and 4 to assess drug compliance, using SPSS for Windows version 11 (SPSS Inc., Chicago, IL, USA). occurrence of adverse effects, and the effectiveness of study treatment. RESULTS

Effectiveness and safety assessments Baseline data of participants The severity of abdominal pain/discomfort and urgency, stool A total of 357 patients were evaluated for study form, and stool frequency were recorded daily using diary cards. Patient-reported global assessment of relief of IBS symptoms, inclusion, with seven patients excluded during the patient-reported assessment of abdominal pain/discomfort, and screening period. A total of 350 patients were random- patient-reported assessment of improvement of abnormal bowel ized to either ramosetron or mebeverine. Data on 343 habits were weekly monitored once every 7 days during the patients were available for the ITT analysis: 175 for 4-week treatment period, compared with the baseline data checked during the 1-week basal period. Data input on a diary ramosetron and 168 for mebeverine. Seven patients were reminded by telephone. The primary endpoint in the study were excluded because of lack of data at week 1 and was the weekly responder rate of patient-reported assessment of later. Demographic and baseline characteristics of relief of IBS symptoms. Patient-reported assessment of relief of study patients are presented in Table 1. Both treatment global IBS symptoms or abdominal pain/discomfort was assessed as follows; 0: completely relieved, 1: considerably relieved, 2: arms were well balanced for gender, age, and the relieved to some extent, 3: unchanged, 4: worsened. A weekly severity of symptoms at baseline. Seven per cent (13/ responder was defined as a patient who was completely relieved or considerably relieved for the previous week, compared with the baseline symptoms. Patient-reported assessment of improvement Table 1 Demographic and baseline characteristics of study patients of abnormal bowel habits was as follows; 0: nearly normalized, 1: considerably relieved, 2: relieved to some extent, 3: unchanged, 4: worsened. A weekly responder for patient-reported assessment Ramosetron Mebeverine of improvement of abnormal bowel habits was defined as a patient Variable (n = 175) (n = 168) P who was nearly normalized or considerably relieved for the Male [no. (%)] 175 (100%) 168 (100%) – previous week, compared with the baseline symptoms. The last Age (mean years ± SD) 43.4 ± 12.1 45 ± 13.1 0.253 7 days of the treatment phase were used as the primary efficacy Height (mean cm ± SD) 171.3 ± 5.7 170.8 ± 5.6 0.422 endpoint. Weight (mean kg ± SD) 68.7 ± 9.4 68.1 ± 8.3 0.582 To identify supportive evidence for the primary outcome, Baseline score (mean ± SD) patient-reported assessment of the severity of each symptom and Abdominal pain/discomfort 1.8 ± 0.7 1.9 ± 0.8 0.304 safety endpoints were determined as secondary outcomes. Safety Bristol stool form score 5.3 ± 1.0 5.5 ± 1.0 0.138 endpoints included the incidence of adverse events leading to Stool frequency (/day) 2.2 ± 1.1 2.5 ± 1.4 0.110 discontinuation and potentially clinically relevant symptoms and Urgency 0.8 ± 1.1 1.0 ± 1.3 0.167 laboratory abnormalities.

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Patients screened: 357

Screening failures: 7 Randomized: 350

Ramosetron group: 175 Mebeverine group: 168 Lack of data: 7

Discontinued: 13 Discontinued: 15 Completed study: 164 Adverse event: 7 Completed study: 153 Adverse event: 4 Consent withdrawn: 2 Consent withdrawn: 3 Lost to follow-up: 1 Lost to follow-up: 1 Protocol violation: 1 Protocol violation: 2 Lack of efficacy: 1 Lack of efficacy: 5

Figure 1 Flowchart of patient progression Evaluation longer Evaluation shorter Evaluation longer Evaluation shorter than 2 weeks: 5 than 2 weeks: 8 than 2 weeks: 5 than 2 weeks: 10 through the study.

175) and 9% (15/168) of patients in the ramosetron and 40 Ramosetron Mebeverine 37.237.5 mebeverine groups, respectively, did not complete the 35 study. The reasons for premature discontinuation in 30 28.3 24.8 the ramosetron and mebeverine groups are shown te (%) 25 in Fig. 1. A total of 167 and 158 randomized patients 20 17.717.3 in the ramosetron and mebeverine groups, respectively, 15 ponder rat 9.6 were evaluated longer than 2 weeks, and included in 10 7.5 Resp the PP analysis. A ﬂowchart of patient progression 5 throughout the study is presented in Fig. 1. 0 Week 1 Week 2 Week 3 Week 4

Patient-reported assessment of relief of IBS Figure 2 The weekly responder rates of ‘Patient-reported assessment of relief of global IBS symptoms’. The responder rates significantly symptoms increased during the study period in both treatment arms (P < 0.001 by 4-sample test for equality of proportions without continuity correc- The proportion of weekly responders for adequate relief tion) The responder rates at the final point in the ramosetron group of global IBS symptoms significantly increased during were not significantly different from those in the mebeverine group the study period in both treatment arms (P < 0.001, (P > 0.05 by Pearson’s chi-squared test). 4-sample test for equality of proportions without continuity correction) (Fig. 2). The responder rates at the final point (last 1 week) for adequate relief of global and mebeverine groups (P < 0.001, 4-sample test for IBS symptoms did not significantly differ between the equality of proportions without continuity correction) ramosetron and mebeverine groups (37% vs 38% on (Fig. 4). The percentage of patients with adequate relief ITT analysis and 36% vs 34% on PP analysis). Fig. 3 of abnormal bowel habits at the last week in the presents the weekly responder rates of ‘Patient- ramosetron group was comparable with that in the reported assessment of relief of abdominal pain/ mebeverine group (36% vs 34% on ITT analysis and discomfort’. The percentage of patients in the ramose- 35% vs 31% on PP analysis). tron and mebeverine groups with adequate relief of abdominal pain/discomfort significantly increased Changes of symptom scores during the study period (P < 0.001, 4-sample test for equality of proportions without continuity correction). Significant decrease in the symptom severity of The responder rates at the last week for adequate relief abdominal pain/discomfort from the baseline was of abdominal pain/discomfort were not significantly observed at each time point in both treatment arms different between the ramosetron and mebeverine (P < 0.001, time effect of RMANOVA). The score of groups (40% vs 35% on ITT analysis and 39% vs urgency was significantly decreased at each time point 32% on PP analysis). The weekly responder rates for in both treatment groups, compared with the baseline adequate relief of abnormal bowel habits significantly score of urgency (P < 0.001, time effect of RMANOVA). increased during the study period in the ramosetron The score of the Bristol stool form scale was

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45 Ramosetron Mebeverine Table 2 Incidence of adverse events and the number of patients 39. 7 40 withdrawn from the study due to adverse events 35.1 35 30.2 Ramosetron Mebeverine 30 27.5 te (%) (n = 175) (n = 168) 25 Adverse event n (%) n (%) P-value 20 18.318.6

ponder rat 15 Gastrointestinal disorders 10.8 Constipation 4 (2) 1 (1) 0.372

Resp 10 7.5 Abdominal pain/discomfort 3 (2) 2 (1) 1.000 5 Neurology 0 Dizziness 1 (1) 1 (1) 1.000 Week 1 Week 2 Week 3 Week 4 Ear, nose and throat Viral infections 0 1 (1) 0.487 Figure 3 The weekly responder rates of ‘Patient-reported assessment Respiratory of relief of abdominal pain/discomfort’. The responder rates Dyspnea 0 1 (1) 0.487 significantly increased during the study period in both treatment arms Skin lesions 2 (1) 0 0.499 (P < 0.001 by 4-sample test for equality of proportions without Musculoskeletal pain 1 (1) 0 1.000 continuity correction) The responder rates at the final point in the Malaise and fatigue 1 (1) 0 1.000 ramosetron group were not significantly different from those in the Pruritus 1 (1) 0 1.000 mebeverine group (P > 0.05 by Pearson’s chi-squared test). Total patients with 13 (7) 6 (4) 0.125 adverse events Patients withdrawn from the 7 (4) 4 (2) 0.149 40 Ramosetron Mebeverine study due to adverse events 36 34. 4 35

30 26.527.5 te (%) 25 was the most commonly recorded adverse event in the 19.5 20 17.3 ramosetron group (2%). Seven patients (4%) in the 15 ramosetron group and four patients (2%) in the meb- ponder rat 1010.8 8 9.3 10 everine group withdrew from the study due to adverse Resp 5 events. The major adverse event associated with these 0 withdrawals in the ramosetron group was constipation Week 1 Week 2 Week 3 Week 4 (3/7). All of the adverse events were described as of

Figure 4 The weekly responder rates of ‘Patient-reported assessment mild or moderate severity. Absence of stool despite the of relief of abnormal bowel habits’. The responder rates significantly use of rescue laxatives was defined as severe constipa- increased during the study period in both treatment arms (P < 0.001 by tion. No serious adverse events such as severe consti- 4-sample test for equality of proportions without continuity correction) The responder rates at the final point in the ramosetron group pation and ischemic colitis were reported in the were not significantly different from those in the mebeverine group ramosetron and mebeverine groups. Laboratory values (P > 0.05 by Pearson’s chi-squared test). were not significantly changed by ramosetron or mebeverine treatment. significantly reduced at each time point in both groups, compared with the baseline score (P < 0.001, time DISCUSSION effect of RMANOVA). Significant decrease in stool frequency from the baseline was noted at each time point This multicenter, randomized, open-label study in in the ramosetron and mebeverine treatment groups male patients with D-IBS demonstrates the efficacy of (P < 0.001, time effect of RMANOVA). The ramosetron ramosetron in relieving abdominal pain/discomfort and mebeverine groups showed significant improve- and improving abnormal bowel habits. The results of ment in symptom scores within the first week of the present study showed similar therapeutic efficacy treatment, which was sustained throughout the sub- of ramosetron, compared with mebeverine. The sequent weeks of treatment (Figures S1,S2,S3,S4). responder rate during the last week based on ‘Patient- reported assessment of relief of global IBS symptoms’ was 37% in the ramosetron group which was compa- Safety rable with that in the mebeverine group (38%). This Adverse events reported during the study are shown in study has a weakness in its design. A tablet of Table 2. Adverse events were reported by 7% (13/175) ramosetron 5 lg was taken once daily before breakfast, and 4% (6/168) of patients in the ramosetron group and whereas a tablet of mebeveine 135 mg was taken three mebeverine group, respectively. This difference was times daily before meals. As IBS patients have a high not statistically significant (P = 0.125). Constipation level of placebo effect, the number of tablets taken

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daily might influence on the belief about the effects of had beneficial effects on abnormal stool consistency drug. Higher numbers of tablets appear to lead to more such as loose or watery stool, increased stool fre- placebo effects. Therefore, it cannot be excluded that quency and urgency as well as on abdominal pain/ mebeverine has additional effects attributed to higher discomfort. numbers of tablets taken daily. In the present study, ramosetron was compared with In the literature, there are only two published mebeverine that is widely used in the management of studies on the clinical trials of ramosetron for the IBS. Mebeverine is known to decrease motility via a treatment of patients with IBS.11,12 A multicenter, direct effect on smooth muscle cells and to have double-blind, dose-ranging phase II study was per- antispasmodic activity and regulatory effects on the formed in Japanese patients with D-IBS, showing that bowel function. Our findings of the present study show 5 lg and 10 lg ramosetron were effective doses for that both ramosetron and mebeverine have beneficial improving IBS symptoms.11 Subsequently, the ran- effects on multiple IBS-D symptoms. Oral administra- domized, double-blind, placebo-controlled phase III tion of mebeverine at the dose of 135 mg t.i.d. was clinical trial of ramosetron was performed in 539 well tolerated without any significant adverse effects. Japanese patients with D-IBS meeting the Rome II A recent systematic review showed no statistically criteria, demonstrating that ramosetron 5 lg once significant efficacy of mebeverine in global improve- daily is effective and well tolerated for the treatment ment of IBS, compared with placebo.13 Thus, it is of patients with D-IBS.12 In that study, the responder uncertain whether mebeverine has any efficacy over rate of ‘Patient-reported assessment of relief of global placebo. However, given that the responder rate at IBS symptoms’ at the end of the first month of week 4 was 38% in the mebeverine group of the treatment in male patients with D-IBS was 33% in the present study and 16% in the placebo group of the ramosetron group and 16% in the placebo group.12 As previous phase III study, in which a similar method- the methodology of the placebo-controlled study ology assessing efficacy parameters was used, mebe- assessing efficacy parameters is similar to that of the verine seems to have therapeutic efficacy in male present study, comparison of responder rates between patients with IBS-D. A previous randomized, double- studies seems to be feasible. The responder rate at blind study for the comparison of alosetron and week 4 was 37% in the ramosetron group of the mebeverine showed that alosetron provided signifi- present study and 16% in the placebo group of the cantly greater therapeutic benefit than mebeverine.14 previous phase III study, suggesting that ramosetron Thirty-nine percent of mebeverine-treated patients has therapeutic efficacy in male patients with IBS-D. showed adequate relief of abdominal pain/discomfort In the previous phase III study, the statistically at week 4 during treatment, which is close to the significant efficacy of ramosetron was demonstrated responder rate in the mebeverine group of the present in male patients, but not in female patients. The study. The proportion of patients with adequate relief reason for a difference in efficacy between men and of abdominal pain/discomfort at week 4 was 46% in women remains unclear. Given that only 18% of the alosetron group, which is higher than that in the enrolled patients were female and the responder rate ramosetron group of the present study (37%). The of placebo at week 12 in female patients was greater reason for this difference in responder rates between than that in male patients (40% vs 24%),12 the ramosetron and alosetron remains to be elucidated. It discrepancy in the therapeutic efficacy of ramosetron can be at least partly explained by the discrepancy in between male and female patients may be explained inclusion criteria, the dose of drug, and evaluation by the small sizes of female patients and a high level methodology. In the alosetron study, non-constipated of placebo effect in females. Further investigation with female IBS patients meeting the Rome I criteria were larger numbers of female patients with IBS-D is included, and alosetron 1 mg was taken twice daily. required. The use of ramosetron is permitted only Whereas, the present study included male patients for male patients with IBS-D in Korea. Hence, in the with diarrhea meeting the Rome III criteria and present study, female patients were excluded from the ramosetron 5 lg was taken once daily. The lower risk study. As all patients enrolled in the study were of ramosetron might be attributed to lower doses or males, placebo effects are less likely to be high. We gender difference, which requires further study. The used the Rome III criteria for the diagnosis of IBS-D, elimination half-life of ramosetron is 9 h which is where subtyping of IBS is based on predominant stool believed to be longer than that of ondansetron (3.5 h) or pattern.15 This subtyping appears to identify more granisetron (4.9 h).16,17 The dose of ramosetron for the homogenous subgroup, compared with the Rome II prevention of chemotherapy-induced emesis and post- criteria. The present study showed that ramosetron operative nausea and vomiting (0.3 mg) is much higher

2011 Blackwell Publishing Ltd 1103 K. J. Lee et al. Neurogastroenterology and Motility

than that used for the treatment of IBS. Although once Our results of the present study show that ramose- daily administration is currently recommended for the tron has similar therapeutic efficacy to mebeverine in treatment of IBS, twice daily administration might male patients with IBS-D. Adverse event profiles of the have greater efficacy. Further investigation on the ramosetron group are comparable with those of the efficacy and safety of ramosetron 5 lg twice daily in mebeverine. Therefore, ramosetron 5 lg once daily is patients with IBS-D is warranted. as effective and safe as mebeverine three times daily in Alosetron is not available in many countries male patients with IBS-D. Further studies on whether including South Korea. Well-designed clinical trials ramosetron is effective for female patients with IBS-D have demonstrated superiority of alosetron over and whether twice daily administration of a ramose- placebo in relieving IBS symptoms.18 Nevertheless, tron 5 lg tablet has greater efficacy in patients with alosetron-treated patients reported adverse events IBS-D are warranted. In addition, larger postmarketing more frequently than placebo-treated patients. As a data need to be collected from now on. greater incidence of severe constipation and ischemic colitis has been reported in patients taking alosetron, ACKNOWLEDGMENTS the use of alosetron is currently regulated. The most common adverse event occurred in ramosetron- This study was supported by Astellas Pharma Korea Inc., Seoul, treated patients was constipation, followed by South Korea. The funding source had no role in the collection, analysis, or interpretation of data or in the decision to submit the abdominal pain/discomfort, which are considered to manuscript for publication. The trial name is CRM (Comparison be related to the effect of the 5-HT3 receptor of ramosetron and mebeverine) and the trial is registered in the antagonist. However, the incidence of constipation Clinical Trial Center of Ajou University Hospital. We thank the in ramosetron-treated patients seems to be much following investigators who participated in the study: I. K. Sung; S. G. Kim; G. A. Song; S. S. Young; M. I. Park; H. S. Kim; S. T. Lee; 12,19 lower than that in alosetron-treated patients. H. Y. Jeong. Furthermore, all of the adverse events occurred in ramosetron-treated patients were mild or moderate in severity. The number of patients who withdrew from AUTHOR CONTRIBUTION the study due to adverse events was only 3%. KJL, NYK, JKK, KCH, OYL, JSL, SCC, CIS, SJM, HJP, MKC, YTB, Neither severe constipation nor ischemic colitis and PLR were involved in study design, collected patients, performed the study and approved the submitted draft; IKS, was reported by ramosetron-treated patients. In the SGK, GAS, SSY, MIP, HSK, STL, and HYJ collected patients, present study, the evaluation of safety was carried performed the study and approved the submitted draft; KJL and out during the 4-week study period. Therefore, long- PLR analyzed the data and wrote the paper. term safety and tolerability associated with ramosetron use in patients with IBS-D should be evaluated CONFLICTS OF INTEREST through the postmarketing survey. As ramosetron was launched in the Korean market in the late 2010, The authors have no competing interests to declare and no financial relationship with the pharmaceutical company. The postmarketing surveillance data are of importance to authors have complete access to the data. confirm its safety.

4 Saito YA, Schoenfeld P, Locke GR III. 7 Camilleri M, Chey WY, Mayer EA REFERENCES The epidemiology of irritable bowel et al. A randomized controlled clini- 1 Croghan A, Heitkemper MM. Recog- syndrome in North America: a sys- cal trial of the serotonin type 3 nizing and managing patients with tematic review. Am J Gastroenterol receptor antagonist alosetron in irritable bowel syndrome. J Am Acad 2002; 97: 1910–5. women with diarrhea-predominant Nurse Pract 2005; 17: 51–9. 5 Camilleri M, Northcutt AR, Kong S irritable bowel syndrome. Arch 2 Wilson S, Roberts L, Roalfe A et al. et al. Efﬁcacy and safety of alosetron in Intern Med 2001; 161: 1733–40. Prevalence of irritable bowel syn- womenwithirritablebowelsyndrome: 8 Miyata K, Ito H, Fukudo S. Involve- drome: a community survey. Br J Gen a randomised, placebo-controlled trial. ment of the 5-HT3 receptor in Pract 2004; 54: 495–502. Lancet 2000; 355: 1035–40. CRH-induce defecation in rats. Am J 3 Gwee KA, Wee S, Wong ML et al. 6 Cremonini F, Delgado-Aros S, Physiol 1998; 274: G827–31. The prevalence, symptom character- Camilleri M. Efﬁcacy of alosetron in 9 Hirata T, Funatsu T, Keto Y et al. istics, and impact of irritable bowel irritable bowel syndrome: a meta- Inhibitory effects of ramosetron, a syndrome in an Asian urban com- analysis of randomized controlled potent and selective 5-HT3-receptor munity. Am J Gastroenterol 2004; 99: trials. Neurogastroenterol Motil 2003; antagonist, on conditioned fear 924–31. 15: 79–86. stress-induced abnormal defecation

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and normal defecation in rats: type 3 receptor antagonist ramosetron nausea and vomiting. Drugs Today comparative studies with antidiar- in both male and female Japanese 2002; 38: 75–89. rheal and spasmolytic agents. J Phar- patients with diarrhea-predominant 17 Gan TJ. Selective serotonin 5-HT3 macol Sci 2008; 106: 264–70. irritable bowel syndrome. Scand J receptor antagonists for postoperative 10 Hirata T, Keto Y, Nakata M et al. Gastroenterol 2008; 43: 1202–11. nausea and vomiting: are they all Effects of serotonin 5-HT3 receptor 13 Jones RH, Holtmann G, Rodrigo L the same? CNS Drugs 2005; 19: 225– antagonists on stress-induced colonic et al. Alosetron relieves pain and 38. hyperalgesia and diarrhoea in rats: improves bowel function compared 18 Andresen V, Montori VM, Keller J a comparative study with opioid with mebeverine in female noncon- et al. Effects of 5-HT3 antagonists on receptor agonists, a muscarinic stipated irritable bowel syndrome symptom relief and constipation in receptor antagonist and a synthetic patients. Aliment Pharmacol Ther non-constipated irritable bowel syn- polymer. Neurogastroenterol Motil 1999; 13: 1419–27. drome: a systematic review and meta- 2008; 20: 557–65. 14 Darvish-Damavandi M, Nikfar S, analysis of randomized controlled 11 Matsueda K, Harasawa S, Hongo M Abdollahi M. A systematic review of trials. Clin Gastroenterol Hepatol et al. A phase II trial of the novel efﬁcacy and tolerability of mebever- 2008; 6: 545–55. serotonin type 3 receptor antagonist ine in irritable bowel syndrome. 19 Rahimi R, Nikfar S, Abdollahi M. ramosetron in Japanese male and World J Gastroenterol 2010; 16: Efﬁcacy and tolerability of alosetron female patients with diarrhea- 547–53. for the treatment of irritable bowel predominant irritable bowel syn- 15 Longstreth GF, Thompson WG, Chey syndrome in women and men: drome. Digestion 2008; 77: 225–35. WD et al. Functional bowel disor- A meta-analysis of eight randomized, 12 Matsueda K, Harasawa S, Hongo M ders. Gastroenterology 2006; 130: placebo-controlled, 12-week trials. et al. A randomized, double-blind, 1480–91. Clin Ther 2008; 30: 884–901. placebo-controlled clinical trial of the 16 Rabasseda X. Ramosetron, a 5-HT3 effectiveness of the novel serotonin receptor antagonist for the control of

SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article: Figure S1. Change in weekly average scores of abdominal pain/discomfort. Significant decrease in the symptom severity from the baseline was observed at each time point in the ramosetron and mebeverine groups (P<0.001 by repeated measures ANOVA). Figure S2. Change in weekly average scores of urgency. Significant decrease in the symptom severity from the baseline was observed at each time point in the ramosetron and mebeverine groups (P<0.001 by repeated measures ANOVA). Figure S3. Change in weekly average scores of Bristol stool form scale. Significant decrease in the stool form score from the baseline was observed at each time point in the ramosetron and mebeverine groups (P<0.001 by repeated measures ANOVA). Figure S4. Change in weekly average stool frequency. Significant decrease in the stool frequency from the baseline was observed at each time point in the ramosetron and mebeverine groups (P = 0.011 and 0.019 by repeated measures ANOVA, respectively). Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.

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