David J. McSorley

Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial

BACKGROUND Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with symptoms of abdominal pain, discomfort, and altered bowel function. Antagonists of the type 3 serotonin receptor (5-HT3) have shown promising results in the relief of IBS-associated symptoms. We aimed to confirm these findings by doing a randomised, placebo-controlled trial. METHODS We studied 647 female IBS patients with diarrhoea-predominant or alternating bowel patterns (diarrhoea and constipation). 324 patients were assigned 1 mg alosetron and 323 placebo orally twice daily for 12 weeks, followed by a 4-week post-treatment period. Adequate relief of abdominal pain and discomfort was the primary endpoint; secondary endpoints included improvements in urgency, stool frequency, and stool consistency. Analysis was by intention to treat. FINDINGS 79 (24%) of patients in the alosetron group and 53 (16%) in the placebo group dropped out. The difference in the drop-out rate between groups was mainly due to a greater occurrence of constipation in the alosetron group. A greater proportion of alosetron-treated patients than placebo-treated patients (133 [41%] vs 94 [29%], respectively) reported adequate relief for all 3 months of treatment (difference 12% [4.7-19.2]). Alosetron also significantly decreased urgency and stool frequency, and increased stool firmness. Constipation occurred in 30% and 3% of patients in the alosetron and placebo groups, respectively. INTERPRETATION Alosetron was well tolerated and clinically effective in alleviating pain and bowel-related symptoms in this population of women with IBS.

Helicobacter pylori infection rates in duodenal ulcer patients in the United States may be lower than previously estimated

OBJECTIVES:Published studies have estimated the rate of Helicobacter pylori (H. pylori) infection in patients with duodenal ulcer disease to be as high as 95%; the majority of remaining duodenal ulcers have been attributed to the use of ulcerogenic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs). We aimed to assess the H. pylori prevalence rates of U.S. duodenal ulcer patients in large, well-controlled studies.METHODS:More than 2900 patients with endoscopically diagnosed non-NSAID duodenal ulcers were enrolled in a series of six placebo-controlled, double-blind studies conducted in the United States that assessed H. pylori using a combination of tests. Patients were considered infected with H. pylori only if culture growth was observed, or both histological and CLOtest results were positive. Patients were considered uninfected if the results of at least two tests were negative. Patients with missing test results, results of only a single test, or conflicting test results were not evaluable for H. pylori assessment.RESULTS:Of the 2394 endoscopically diagnosed evaluable duodenal ulcer patients, 73% (1737) were confirmed infected with H. pylori at study entry.CONCLUSIONS:The results of six carefully designed and controlled studies suggest that an assumed H. pylori infection rate of approximately 95% may overestimate the actual rate of H. pylori infection in duodenal ulcer patients in the United States. Although H. pylori infection is an important factor in the etiology of noniatrogenic duodenal ulcer disease, other factors may predominate in some patients and should not be overlooked in determining an appropriate course of treatment. The empiric use of antibiotic therapy for ulcer patients without confirmation of the presence of H. pylori cannot be recommended.

Clarithromycin-resistant helicobacter pylori in patients with duodenal ulcer in the united states

Background:Clarithromycin is a key component of several antimicrobial treatment regimens for Helicobacter pylori. Cure rates with clarithromycin-containing regimens are significantly decreased when resistance is present. Resistance develops by a point mutation in the ribosomal RNA of some organisms exposed to clarithromycin. We studied the prevalence of clarithromycin-resistant organisms in patients with duodenal ulcer in the United States from 1993–96.Methods:Patients with endoscopic evidence of a duodenal ulcer were studied. Gastric biopsies were cultured for H. pylori and antimicrobial sensitivity was determined by the E-test (epsilometer agar diffusion gradient).Results:In 1993–94, three of 78 patients (4%) had clarithromycin-resistant strains of H. pylori. In 1995–96, 44 of 348 patients (12.6%; p= 0.025) had resistant strains of H. pylori. Patients who had previously failed antimicrobial treatment for H. pylori accounted for much of the increase in resistant strains (25%).Conclusions:Failed therapy with clarithromycin-based regimens is a growing cause of antimicrobial resistance in H. pylori in the United States. Whereas the overall rates of primary resistance are low, the increase in secondary resistance over a short period of time is worrisome. New treatments that prevent the emergence of resistance may be important in the future.

Alosetron improves quality of life in women with diarrhea-predominant irritable bowel syndrome

OBJECTIVES:The aim of this study was to assess the impact of alosetron, a treatment recently approved in the United States for irritable bowel syndrome in diarrhea-predominant female patients, on health-related quality of life.METHODS:Quality of life was assessed as part of two 12-wk randomized, double-blind, placebo-controlled irritable bowel syndrome studies comparing alosetron 1 mg b.i.d. with placebo (S3BA3001 and S3BA3002). Patients completed a validated disease-specific quality of life questionnaire, the Irritable Bowel Syndrome Quality of Life Questionnaire (IBSQOL), at baseline and at the 12-wk or final visit. The clinical relevance of data were also evaluated by a minimal meaningful difference instrument.RESULTS:A total of 626 and 647 patients were enrolled in studies S3BA3001 and S3BA3002, respectively. Approximately 70% of patients in each study had diarrhea-predominant IBS. In diarrhea-predominant patients enrolled in S3BA3001, statistically significant (p < 0.05) improvements with alosetron versus placebo were observed on all nine IBSQOL scales (emotional health, mental health, sleep, energy, physical functioning, food/diet, social functioning, role–physical, and sexual relations) and for all but one scale (mental health) in S3BA3002. In both studies, a significantly greater percentage of patients treated with alosetron (p < 0.05) experienced clinically meaningful improvement on three of the nine IBSQOL scales (food/diet, social functioning, and role–physical) compared with patients treated with placebo. Patients treated with alosetron did not show worsening in any quality of life domain compared with patients treated with placebo.CONCLUSIONS:These results in women with diarrhea-predominant IBS demonstrate that alosetron significantly improves health-related quality of life.

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 (≤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.

Ranitidine Bismuth Citrate Plus Clarithromycin: A Dual Therapy Regimen for Patients with Duodenal Ulcer

The combination of ranitidine bismuth citrate (RBC) and clarithromycin (CLR) was compared with each treatment alone for the eradication of H. pylori and healing of duodenal ulcers in patients infected with H. pylori.

Effects of sucralfate and ranitidine on aluminum concentrations in elderly volunteers

Elevated aluminum concentrations have been implicated in several disease states in the elderly. We examined the effects of sucralfate, a basic aluminum salt of sucrose sulfate, and ranitidine, administered individually and in combination, on plasma and urine aluminum concentrations in the elderly in a prospective, randomized, three‐arm crossover study. Subjects were 20 healthy volunteers over age 65 years, with no clinically significant comorbidities or recent use of aluminum‐containing drugs or histamine (H)2‐antagonists. The three regimens were ranitidine 300 mg at bedtime, sucralfate 1 g 4 times/day, and ranitidine 300 mg at bedtime plus sucralfate 1 g 4 times/day, administered for 4 weeks, with a washout period of at least 1 week between regimens. Plasma and urine aluminum concentrations were measured on days 0, 1, 7, 14, and 28 of each regimen. After 28 days, mean plasma aluminum concentrations were significantly higher in subjects receiving sucralfate alone (8.5 ± 1.8 μg/L) and sucralfate plus ranitidine (5.1 ± 1.3 μg/L) compared with those receiving ranitidine alone (2.4 ± 0.7 μg/L). Urine aluminum concentrations were significantly higher in subjects receiving sucralfate alone (133.2 ± 32.8 μg/g creatinine) and sucralfate plus ranitidine (148.1 ± 51.9 μg/g creatinine) compared with those receiving ranitidine alone (11.0 ± 3.7 μg/g creatinine). There was no significant difference in plasma or urine aluminum concentrations between subjects who received sucralfate alone versus those who received sucralfate plus ranitidine. Sucralfate 4 g/day in elderly subjects produces a significant increase in both plasma and urine aluminum concentrations, compared with ranitidine 300 mg/day. This increase most likely is secondary to gastrointestinal absorption of aluminum in the sucralfate formulation. The clinical relevance of this increase requires further evaluation.

An Alternative Non-Macrolide, Non-Imidazole Treatment Regimen for Curing Helicobacter pylori and Duodenal Ulcers: Ranitidine Bismuth Citrate Plus Amoxicillin

Background. Because patients who fail to be cured of H. pylori infection following macrolide or imidazole therapy are difficult to treat, there is a clear need for a reasonably effective and simple second‐line treatment regimen. The purpose of these two studies was to evaluate the efficacy of ranitidine bismuth citrate (RBC) plus amoxicillin for the cure of H. pylori infection and for healing duodenal ulcers and preventing ulcer relapse.

Twice‐Daily Versus Thrice‐Daily Clarithromycin in Combination with Ranitidine Bismuth Citrate in the Eradication of Helicobacter pylori

Background. Ranitidine bismuth citrate (RBC), 400 mg bid for 4 weeks, plus clarithromycin, 500 mg tid, is a regimen approved by the US Food and Drug Administration for the eradication of Helicobacter pylori in patients with duodenal ulcers. Proof that the clarithromycin portion of the regimen could be given twice daily without loss of efficacy would reduce cost and improve patient compliance. The objective of this study was to compare the H. pylori eradication rates in patients who had duodenal ulcer and were randomly assigned to 4 weeks of treatment with RBC, 400 mg bid, in conjunction with 2 weeks of therapy with either clarithromycin, 500 mg tid, or clarithromycin, 500 mg bid.

The continued use of placebo-controlled clinical trials in the study of peptic ulcer disease : A sponsor perspective

Investigators and institutional reviews boards who/which have participated in recent controlled gastroenterology clinical research studies assessing new therapies for peptic ulcer disease have questioned the continued use of a placebo-control when efficacious therapies for peptic ulcer disease are currently available. As the sponsor of such studies, Glaxo is of the opinion that the use of placebo-controlled clinical research studies is appropriate in certain situations. In choosing between the use of an active comparator or placebo-controlled trial Glaxo recommends an assessment of the severity of the disease and the morbidity associated with use of placebo treatment. It further recommends the need to assess the efficacy of placebo therapy to establish the baseline remission rate for the disease. Glaxo suggests an assessment of the safety data for the new chemical entity under investigation, and if such data are lacking, minimize patient risk employing suggested study designs that maximize patient utilization. The statistical implications of sample size and the risks associated with Type I and II errors by comparing the number of patients required for a typical study using a placebo and active control are discussed. Finally, for all placebo-controlled studies performed with patients with peptic ulcer disease, the elimination of high risk patients, the use of supplemental antacids, and proper obtainment of informed patient consent is recommended.