Personal view: adequate relief as a primary endpoint in irritable bowel syndrome.

The success of a clinical trial is judged by achieving statistical and clinical significance on the primary endpoint. This is particularly relevant in those trials that are initiated to achieve regulatory approval of a new therapeutic agent. Selection of an endpoint for which statistical significance will be too difficult to achieve can result in clinical trial data that fails to meet regulatory requirements for product approval. Over the past decade, significant progress has been made in development and refinement of the study design for evaluating new therapeutic agents targeted for the treatment of irritable bowel syndrome. One aspect of trial design that has been advanced is recognition of the endpoint of 'Adequate Relief.' Adequate relief has been used as a primary endpoint in treatment trials with alosetron, cilansetron and dextofisopam. With each of these agents, statistically significant benefit was seen when compared to placebo. As an endpoint, adequate relief is responsive, reproducible and moves in the same direction as other meaningful measures, and, therefore, displays properties of a validated endpoint. Adequate relief should be considered an acceptable primary endpoint by regulatory agencies for use in clinical trials of novel therapeutic agents for irritable bowel syndrome.

Stability of irritable bowel syndrome using a Rome II-based classification.

BACKGROUND: As there is no biological marker for irritable bowel syndrome, a diagnosis is made using symptom-based criteria. AIM: To evaluate the stability of self-reported symptoms consistent with Rome II-based irritable bowel syndrome classification. METHODS: Irritable bowel syndrome subjects identified in a 2001 population-based study by modified Rome II criteria were re-contacted 2 years later. Data were collected via a web-based questionnaire. RESULTS: Of the 697 subjects, 30% remained in the same irritable bowel syndrome subtype in both surveys, 18.4% changed irritable bowel syndrome subtype and 52% no longer met the irritable bowel syndrome criteria at follow-up. Subjects continuing to meet the irritable bowel syndrome criteria were more likely to have been initially classified in the alternating irritable bowel syndrome subtype and had more psychological impairment and lower irritable bowel syndrome-related quality of life than subjects not fulfilling the irritable bowel syndrome criteria at follow-up. Lack of pain caused more subjects to fall out of the irritable bowel syndrome criteria than the absence of non-painful bowel symptoms. However, the majority of subjects that did not fulfill the pain component of the irritable bowel syndrome criteria continued to report abdominal pain of at least moderate severity. CONCLUSION: In a US population-based follow-up study using modified Rome II criteria, we found irritable bowel syndrome is episodic in nature and current classification is limited in capturing fluctuation of disease over time.

Determinants of healthcare-seeking behaviour among subjects with irritable bowel syndrome.

BACKGROUND: Doctor visits for irritable bowel syndrome are associated with high medical costs. Predictors of medical consultation for irritable bowel syndrome remain poorly understood. AIM: To determine factors associated with healthcare seeking for irritable bowel syndrome. METHODS: Subjects from previous US population-based survey were contacted 2 years later. Those who continued to have irritable bowel syndrome were included. RESULTS: 49% of subjects sought medical care for abdominal symptoms in the past year. Healthcare seeking did not differ significantly between males and females, but more females received an irritable bowel syndrome diagnosis. Predictors of irritable bowel syndrome healthcare seeking differed by gender. In multivariate analysis, age > or = 55 years (OR = 2.8, 95% CI: 1.5-5.4), fear abdominal symptoms relates to serious illness (OR = 1.7, 95% CI: 0.95-3.1), decreased bowel movements (OR = 1.8, 95% CI: 0.98-3.2), dyspepsia (OR = 1.7, 95% CI: 0.94-3.2) and pelvic pain (OR = 2.3, 95% CI: 1.2-4.4) were associated with seeking care in females. Among males, being disabled (OR = 11.6, 95% CI: 2.4-56.1) and abdominal cramping (OR =4.3, 95% CI: 1.2-15.4) were associated with seeking care. Healthcare seekers had lower irritable bowel syndrome-related quality of life. Neither pain severity nor mental health status was associated with seeking care. CONCLUSION: Healthcare-seeking behaviour among irritable bowel syndrome patients was determined by presence of comorbidities and extent that irritable bowel syndrome affected quality of life, not physical symptoms or mental health status.

Prevalence and demographics of irritable bowel syndrome: results from a large web-based survey.

BACKGROUND: Irritable bowel syndrome is a common gastrointestinal disorder, and its prevalence and demographics have been evaluated by different methodologies with varying results. AIM: To evaluate irritable bowel syndrome demographic and prevalence characteristics utilizing a web-enabled panel. METHODS: From an existing 150 000-member panel, 31 829 individuals were randomly selected and sent screening questionnaires to evaluate irritable bowel syndrome symptoms. Individuals who agreed to participate and completed the screening questionnaire received a second questionnaire related to a diagnosis of irritable bowel syndrome, a more detailed symptom description, and additional burden of illness data. RESULTS: Irritable bowel syndrome prevalence was 7%. Prevalence was higher in women vs. men, unmarried individuals vs. married individuals and unemployed individuals vs. employed individuals. Of those completing the second questionnaire, 51% had seen their physicians for irritable bowel syndrome symptoms in the past year and most had an episode within the past 3 months. During the past year, approximately half of the participants had used a prescription medication, and over 90% had used an over-the-counter medication for irritable bowel syndrome. Participants with irritable bowel syndrome demonstrated quality-of-life reductions relative to norms of the United States population. CONCLUSIONS: Web-enabled data collection represents a novel tool for rapidly surveying a large population of individuals with irritable bowel syndrome symptoms.

Review article: the safety and efficacy of alosetron, a 5-HT3 receptor antagonist, in female irritable bowel syndrome patients.

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal-related conditions. In this review, the safety and efficacy of alosetron, a potent and selective 5-HT3 receptor antagonist, in the treatment of IBS are discussed. Alosetron has been shown to produce statistically significant improvements in abdominal pain, stool consistency, stool frequency and urgency in female IBS patients. By contrast, no consistent improvement has been seen in male IBS patients treated with alosetron. The only adverse event of note with alosetron was constipation, and this represents a class effect of 5-HT3 receptor antagonists. In conclusion, alosetron is a safe and effective treatment for female IBS patients.

Review article: evaluation of drugs in experimental gut distension models.

Distension of the gastrointestinal tract elicits abdominal pain, as well as sensations such as discomfort or fullness. Many patients with irritable bowel syndrome have been reported to show a reduced threshold to the pain or discomfort due to experimental rectal distension. This hypersensitivity of the gut may be characteristics of the irritable bowel, as well as other functional gastrointestinal disorders. Intestinal distension in animals induces a range of responses which have been used as indexes of visceral nociception. This paper reviews a recently introduced canine model used to assess the antinociceptive properties of a novel 5-HT3 receptor antagonist, alosetron.

A dose-ranging, placebo-controlled, randomized trial of alosetron in patients with functional dyspepsia.

BACKGROUND: Functional dyspepsia is characterized by upper abdominal pain or discomfort. AIM: To assess the benefit of the 5-HT3-receptor antagonist alosetron in a pilot, dose-ranging, placebo-controlled, multicentre, randomized clinical trial. METHODS: A total of 320 functional dyspepsia patients received placebo (n=81), or alosetron 0.5 mg b.d. (n=77), 1.0 mg b.d. (n=79) or 2.0 mg b.d. (n=83) for 12 weeks, followed by 1 week of follow-up. Primary efficacy was the 12-week average rate of adequate relief of upper abdominal pain or discomfort. Secondary endpoints assessed pain and upper gastrointestinal symptoms. RESULTS: Twelve-week average rates of adequate relief of pain or discomfort were 46% (95% CI: 37-54%), 55% (95% CI: 46-63%), 55% (95% CI: 47-64%) and 47% (95% CI: 38-55%) in the placebo, 0.5 mg, 1.0 mg and 2.0 mg alosetron groups, respectively. Alosetron 0.5 mg or 1.0 mg showed potential benefit over placebo for early satiety and postprandial fullness. Females showed greater responses compared to males. Patients with adequate relief had significantly (P < 0.001) greater reductions in severity and frequency of functional dyspepsia symptoms than those without adequate relief. Constipation was the most commonly reported adverse event. CONCLUSIONS: Alosetron showed potential benefit in relieving functional dyspepsia symptoms compared to placebo. Patients with adequate relief of upper abdominal pain or discomfort showed improvements in multiple functional dyspepsia symptoms.

Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist.

BACKGROUND: No currently available treatment provides consistent relief of irritable bowel syndrome. Colonic sensory and motor function are modulated partly through 5HT3-receptors. AIM: To evaluate effects of the 5HT3-receptor antagonist, alosetron, in irritable bowel syndrome. METHODS: Randomized, double-blind, placebo-controlled, dose-ranging (1, 2, 4, 8 mg b.d. alosetron), 12-week trial in 370 patients with diarrhoea-predominant or alternating constipation and diarrhoea irritable bowel syndrome. Weekly measurement of adequate relief was the key end-point; other irritable bowel syndrome symptoms were collected daily using an electronic phone system. RESULTS: Alosetron (1 mg or 2 mg b.d.) significantly (P < 0.05 vs. placebo) increased the proportion of females, but not males, reporting adequate relief. Stool consistency, frequency and percentage days with urgency improved over placebo (P < 0.05) within the first month with all doses of alosetron, and persisted throughout the trial with all doses in female patients. With 1 mg b.d. alosetron, females had improved stool consistency and urgency within the first week, and adequate relief and improved stool frequency within the first 2 weeks. There was no consistent improvement in bowel function among male patients. CONCLUSION: In female irritable bowel syndrome patients with predominant diarrhoea or alternating constipation and diarrhoea, alosetron is effective in treatment of abdominal pain and discomfort and bowel-related symptoms.

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.

Inhibition of K+ channel activity by 4-AP stimulates N-type Ca2+ channels in CHP-100 cells.

The potassium channel blocker, 4-aminopyridine (4-AP), stimulates neurotransmitter release via plasma membrane depolarization and subsequent activation of voltage-gated calcium channels. The present study assessed the effects of 4-AP on intracellular calcium levels in the human neuroblastoma cell line CHP-100. Blockade of K+ channels with 4-AP significantly increased intracellular calcium concentration ([Ca2+]i). This increase occurred via activation of plasma membrane Ca2+ channels. The 4-AP induced rise in [Ca2+]i was not inhibited by the L-type Ca2+ channel blocker nifedipine but was sensitive to the N-type Ca2+ channel blocker omega-contotoxin GVIA. Tetrodotoxin did not alter the effect of 4-AP. These results suggest that in CHP-100 cells, following inhibition of K+ channels by 4-AP, N-type Ca2+ channels are activated.

Inhibitors of ATP-sensitive potassium channels stimulate intestinal cholecystokinin secretion.

Recently, a role for adenosine 5'-triphosphate(ATP)-sensitive potassium channels in the regulation of cholecystokinin (CCK) secretion has been described in STC-1 cells, an intestinal CCK-secreting cell line. To examine whether a similar mechanism might participate in the regulation of hormone secretion from native CCK cells, the effects of two established inhibitors of ATP-sensitive potassium channels (e.g. glucose, disopyramide) were examined on CCK release from dispersed murine intestinal cells. Both glucose and disopyramide were found to stimulate CCK secretion. Furthermore, CCK release induced by glucose was inhibited by the calcium channel blocker diltiazem. It is concluded that, ATP-sensitive potassium channels may play a role in the regulation of intestinal CCK secretion.

Modulation of colonic motility by substance P, cholecystokinin and neuropeptide Y.

The effects of substance P, cholecystokinin and neuropeptide Y were examined on rabbit distal colonic motility. All three agents produced increased contractile activity but the mechanisms responsible differed depending on the agent tested. In the intact animal, peptide effects were measured under basal conditions and following exposure to atropine, tetrodotoxin and the alpha-adrenergic antagonist phentolamine. Administration of all three peptides resulted in a stimulation of colonic motility. Phentolamine did not significantly effect substance P-, cholecystokinin- or neuropeptide Y-induced activity. By contrast, the in vivo activity induced by cholecystokinin and neuropeptide Y, but not substance P, was nearly eliminated by tetrodotoxin. Only the neuropeptide Y response was partially atropine sensitive. In isolated colonic strips, cholecystokinin-induced activity, but not that produced by neuropeptide Y or substance P, was blocked by tetrodotoxin. Atropine did not significantly inhibit any of the hormone-induced contractions.

Electrophysiology of intestinal cholecystokinin secretion.

The control of gastrointestinal CCK secretion may occur at several points. A decrease in potassium conductance may depolarize the plasma membrane, activating calcium channels with a resultant stimulation in CCK release. The opposite may occur with increases in potassium conductance. The model presented in Fig. 8 suggests that the key control point in the understanding of CCK secretion is the regulation of L-type calcium channels. Whether a single second messenger pathway may regulate calcium channels stimulated by agents such as glucose, phenylalanine, bombesin and cAMP is an important area to pursue.

Modulation of electrical activity in gastrointestinal smooth muscle by peptides.

A rise in intracellular calcium is the predominant signal that leads to the activation of the contractile machinery in gastrointestinal smooth muscle. The primary sources of activating calcium are illustrated in Fig. 2. Voltage- and peptide-mediated release of intracellular calcium contribute to activation of some gastrointestinal smooth muscles. However, the primary source of activating calcium appears to be an influx of calcium across the plasma membrane. The degree of modulation of electrical activity by peptides varies depending upon the region of the gastrointestinal tract studied. Second messenger systems are undoubtly involved in the transduction pathway for receptor-mediated changes in ion channel activity in gastrointestinal smooth muscle. However, in comparison to other excitable cell types, little is known about the coupling mechanisms whereby peptide-receptor binding alters ion channel activity in gastrointestinal smooth muscle. This represents one of the challenging areas to be studied in the field of gastrointestinal smooth muscle. One disease in which a better appreciation of the regulation of ion channel activity could lead to therapeutic benefit is irritable bowel syndrome. A coupling of smooth muscle electrical activity to hypermotility in irritable bowel syndrome has been reported. CCK increases the level of spike activity which triggers hypermotility [40]. It would follow that inhibition of calcium influx should reduce spiking and, therefore, hypermotility. In fact, the calcium channel blockers nifedipine and nicardipine have been shown to decrease colonic motility in irritable bowel syndrome patients [62-64]. As our understanding of gastrointestinal smooth muscle ion channels expands, development of a gastrointestinal selective calcium channel blocker may be possible. This class of agents would be effective in the treatment of irritable bowel syndrome and potentially other peptide-related spastic smooth muscle disorders.

Potentiation of colonic contractility to cholecystokinin and other peptides.

Changes in colonic contractility were studied in anesthetized cats following the intravenous injection of several peptides. Increases in contractile activity were observed after the octapeptide of cholecystokinin (CCK-8), pentagastrin, substance P or neurotensin. On the other hand, vasoactive intestinal peptide (VIP) caused an inhibition which, in some cases, was followed by an excitatory response. The responses produced by pentagastrin, substance P or neurotensin, but not by CCK-8, were partially inhibited by atropine. Following bethanechol pretreatment, the stimulation in contractile activity elicited by CCK-8, substance P, neurotensin or pentagastrin was markedly enhanced. Responses were also increased by pretreatment with eserine, hexamethonium or mecamylamine. This potentiation was blocked by atropine. It is concluded that, following treatments which cause an increase in the level of cholinergic input to the colon, an exaggerated motor response to some peptides can develop.

Voltage and receptor mediated contractile activity of colonic smooth muscle in calcium-free solution.

Normal mechanical activity of cat colonic muscle segments was abolished during incubation in calcium-free solution. In calcium-free solution, contractions could be induced by direct electrical stimulation or by depolarization with high potassium. In high potassium calcium-free solution, carbachol also induced an additional contractile response due to muscarinic receptor occupation. It is concluded that in colonic smooth muscle, depolarization mediated, as well as receptor mediated, release of intracellular calcium occurs.

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.

Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation - a 4-week, randomized, double-blind, placebo-controlled, dose-response study.

BACKGROUND: Velusetrag is an orally active 5-HT(4) receptor agonist of potential benefit in treating chronic idiopathic constipation. AIM: To evaluate the efficacy, safety and tolerability of velusetrag in chronic idiopathic constipation. METHODS: After a 2-week baseline period, patients [<3 spontaneous bowel movements (SBM)/week] received placebo or velusetrag (15, 30 or 50 mg) daily for 4 weeks in a randomized, double-blind design, followed by a 1-week follow-up period. The primary endpoint was the change from baseline in weekly SBM frequency averaged over the 4-week treatment period. RESULTS: Patients receiving velusetrag (15, 30 and 50 mg) achieved statistically and clinically significant increases in weekly SBM frequency relative to those receiving placebo. Mean increases were 3.6, 3.3 and 3.5 SBM/week respectively, compared with 1.4 SBM/week for placebo (P < 0.0001). Statistically significant increases in the weekly frequency of complete SBM (CSBM) were also reported (mean increases of 2.3, 1.8 and 2.3 for 15, 30 and 50 mg velusetrag respectively, compared with 0.6 for placebo). Common adverse events associated with velusetrag were diarrhoea, headache, nausea and vomiting, generally occurring during the initial days of dosing. CONCLUSION: Velusetrag was efficacious and well tolerated in patients with chronic idiopathic constipation (ClinicalTrials.gov identifier NCT00391820).