Tolerability and safety of alosetron during long-term administration in female and male irritable bowel syndrome patients.

OBJECTIVES: Alosetron (Lotronex) is a new therapeutic agent for irritable bowel syndrome (IBS) in women with diarrhea-predominant IBS. This multicenter randomized, double-blind, placebo-controlled study assessed the safety and tolerability of alosetron during long-term (< or = 12 months) treatment. METHODS: A total of 859 subjects (637 female and 222 male) with IBS were enrolled from 130 sites in the United States and were randomized 3:1 to receive 1 mg alosetron or placebo b.i.d. for 48 wk; of the subjects, 649 (76%) were randomized to the alosetron group and 212 (24%) to the placebo group. Of the original group, 850 subjects received at least one dose of alosetron (n = 640) or placebo (n = 210). RESULTS: In all, 59% of the subjects completed the study. Safety data were similar in treatment groups and within age, sex, racial origin, and hormone use. Adverse events were reported by 83% (530/640) and 76% (159/210) of subjects in the alosetron and placebo groups, respectively, (p < 0.05) and were similar with the exception of constipation; 32% of subjects receiving alosetron reported constipation, compared to 5% in the placebo group (p < 0.001). Most reports (72%) of constipation were of mild or moderate severity, and 66% of subjects with constipation had single episode of 8 days median duration. Constipation occurred a median of 13 days after initiating treatment and resolved spontaneously, with laxative, or after a brief interruption of therapy. Of the subjects, 4% (11/210) in the alosetron and 5% (28/ 640) in the placebo group experienced serious adverse events. Two deaths occurred in subjects with pre-existing cardiovascular risk factors; neither death was attributed to the study drug. CONCLUSIONS: Alosetron 1 mg b.i.d. for 12 months was well tolerated. Constipation is the most frequent adverse event, with a higher incidence of transient constipation in alosetron-treated patients, typically occurring in the first month of treatment.

Additional investigations fail to alter the diagnosis of irritable bowel syndrome in subjects fulfilling the Rome criteria.

OBJECTIVE: Irritable bowel syndrome (IBS) is diagnosed by the presence of a constellation of symptoms fulfilling the Manning or Rome Criteria, after exclusion of organic disease. To exclude other diagnoses that might contribute to the abdominal pain or bowel symptoms experienced by subjects with IBS, numerous screening algorithms have been advocated, incorporating lactose hydrogen breath tests, thyroid function tests, fecal ova and parasite determination, and colonic endoscopy/radiography. The utility of these tests in uncovering alternative diagnoses, other than IBS, was examined in 1452 patients. METHODS: Data were combined from two large multinational studies of IBS patients. All patients exhibited symptoms meeting the Rome criteria for IBS for at least 6 months before study entry. If prior evaluation had been > 2 yr previously, patients underwent colonic endoscopy/radiography at study entry. In addition, thyroid function tests, fecal ova and parasite determination, and a lactose hydrogen breath test were performed. RESULTS: Lactose malabsorption was diagnosed in 23% (256/1122) of patients. Colonic abnormalities were detected in 2% (7/306) of patients; in four patients, colonic inflammation (n = 3) or obstruction (n = 1) may have contributed to symptoms of abdominal pain or altered bowel habits. Abnormal thyroid-stimulating hormone levels were detected in 6% (67/1209) of patients, of whom half were hypothyroid and half were hyperthyroid. Positive fecal ova and parasite tests were noted in 2% (19/1154) of patients. CONCLUSIONS: Examination of screening tests in 1452 patients with an established history of IBS revealed an incidence of lactose malabsorption comparable to that in the general U.S. population and a low incidence of thyroid dysfunction, ova and parasite infestation, or colonic pathology. The limited detection rates, added costs, and inconvenience of these tests suggest that their routine use in the diagnostic evaluation of established IBS patients should be scrutinized.

Adequate relief as an endpoint in clinical trials in irritable bowel syndrome.

Irritable bowel syndrome is characterized by recurrent abdominal pain and altered bowel function. In designing studies to evaluate new treatments for this disease, however, it is difficult to select appropriate endpoints to reflect improvement in the range of symptoms of the syndrome. In the present study we evaluated the parameter of adequate relief of abdominal pain and discomfort, as perceived by the patients, as a key endpoint for efficacy in the treatment of patients with irritable bowel syndrome. Abdominal pain and bowel function data were collected daily from 370 patients with the disease during treatment with placebo or a novel potent 5HT3 receptor antagonist. Once every 7 days adequate relief of pain and discomfort was assessed. Quality-of-life data were collected using self-administered questionnaires. The endpoint of adequate relief was significantly (P < 0.05) correlated with improvement in pain severity scores, percentage of pain-free days, percentage of days with urgency, improvement in stool frequency and consistency, and quality-of-life parameters. Adequate relief of pain and discomfort is significantly correlated with changes in multiple parameters associated with irritable bowel syndrome and can be used as an endpoint for assessing response to therapy in these patients.

Use of a novel electronic data collection system in multicenter studies of irritable bowel syndrome.

BACKGROUND: The reliability of symptom data collected during efficacy studies in irritable bowel syndrome (IBS) is paramount to the proper assessment of potential therapeutic agents. Historically, data have been collected on paper diary cards, which patients were requested to fill out at a specified interval. However, with paper diary cards it is not possible to determine whether the cards are filled out as required, or at random times. To circumvent this problem, a novel electronic data collection system that ensures the reliability and security of data entry was used. METHODS: Data were collected from 640 patients during the 2-week screening and 12-week treatment phases of two multicentre trials of IBS. The electronic data collection system used was based upon a touchtone telephone system. RESULTS: The electronic data collection system had a potential 8135 up-time hours during the study. An up-time of 8040 h and down-time of 95 h was observed. This corresponds to an up-time of approximately 99%. Patient compliance for data entry in the two studies was 81% and 83%, respectively. On a single random day during their daily telephone call, patients were asked questions to assess satisfaction with the system. On aggregate, 79% of patients were satisfied or very satisfied with the system, only 10% were dissatisfied or very dissatisfied. CONCLUSION: A unique electronic data collection system was tested for use in clinical studies in IBS. This system provided 100% reliability as to the date of data entry, and data were not subject to modification once entered. This methodology represents a marked advancement in clinical studies of IBS.