Trials In Irritable Bowel Syndrome Research Articles

Reports of "Satisfactory Relief" by IBS Patients Receiving Usual Medical Care Are Confounded by Baseline Symptom Severity and Do Not Accurately Reflect Symptom Improvement

Treatment trials for irritable bowel syndrome (IBS) usually define a responder as a patient who reports satisfactory relief or adequate relief of symptoms at the end of the trial. However, these measures have not been adequately validated. (1) Compare a binary satisfactory relief measure to alternative ways of defining a treatment responder. (2) Determine whether baseline IBS symptom severity or psychological distress influence the sensitivity of these outcome measures. A total of 350 patients (81% females, average age 50 yr) who had a medical diagnosis of IBS and satisfied Rome II criteria, were recruited from Group Health Cooperative of Puget Sound. At baseline the Irritable Bowel Severity Scale (IBSS) was used to assess symptom severity and to classify patients as mild, moderate, or severe. Psychological distress and IBS-specific quality of life (IBS-QOL) were also assessed. After 6 months treatment with standard medical care, IBSS and IBS-QOL were reassessed, and patients were asked whether they had experienced satisfactory relief and whether they were somewhat or markedly better. Initial severity of IBS significantly affected the proportion who reported satisfactory relief (mild, 72%; moderate, 53%; severe, 44%) and the proportion who were somewhat or markedly better (mild, 62%; moderate, 44%; severe, 38%), but did not affect the proportion with a 50% reduction in symptoms (mild, 26%; moderate, 25%; severe, 23%). Although mild patients were the most likely to report satisfactory relief, they showed no average decrease in symptom severity or improvement in IBS-QOL. Conversely, severe patients, who were the least likely to report satisfactory relief, had the largest reductions in IBS symptom severity and the largest improvements in IBS-QOL. Psychological distress had no significant effect on the responder rate after adjusting for IBS symptom severity. These data from a descriptive study suggest that satisfactory relief is confounded with initial IBS symptom severity and is poorly correlated with the amount of symptom improvement. Confirmation of these findings in a clinical trial is needed.

Design of Treatment Trials for Functional Gastrointestinal Disorders

This document addresses the design of trials to assess the efficacy of new treatments for functional gastrointestinal disorders (FGID), emphasizing trials in irritable bowel syndrome and dyspepsia, because most research has been undertaken in these conditions. The double-blind, randomized, placebo-controlled, parallel group trial remains the preferred design. Randomized withdrawal designs, although encouraged by the European Agency for the Evaluation of Medicinal Products, have the same potential disadvantages as a crossover design, including carryover effects, unmasking (unblinding), and overestimation of the potential benefit for clinical practice. Innovative trial designs that evaluate intermittent (on demand) treatment are likely to become more common in the future. Investigators should include as broad a spectrum of patients as possible and should report recruitment strategies, inclusion/exclusion criteria, and attrition data. The primary analysis should be based on the proportion of patients in each treatment arm who satisfy an a priori treatment responder definition, or a prespecified clinically meaningful change in a patient-reported symptom improvement measure. Such measures of improvement are psychometrically validated subjective global assessments or a change from baseline in a validated symptom severity questionnaire. It is unethical to change the responder definition after a trial begins. Data analysis should address all patients enrolled, using an intention-to-treat principle. Reporting of results should follow the Consolidated Standards for Reporting Trials guidelines and include an analysis of harms data and secondary outcome measures to support or explain the primary outcome. Trials should be registered in a public location, prior to initiation, and should be published even if the results are negative or inconclusive.

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The placebo effect in irritable bowel syndrome trials: a meta‐analysis1

Despite the apparent high placebo response rate in randomized placebo-controlled trials (RCT) of patients with irritable bowel syndrome (IBS), little is known about the variability and predictors of this response. To describe the magnitude of response in placebo arms of IBS clinical trials and to identify which factors predict the variability of the placebo response. We performed a meta-analysis of published, English language, RCT with 20 or more IBS patients who were treated for at least 2 weeks. This analysis is limited to studies that assessed global response (improvement in overall symptoms). The variables considered as potential placebo modifiers were study design, study duration, use of a run-in phase, Jadad score, entry criteria, number of office visits, number of office visits/study duration, use of diagnostic testing, gender, age and type of medication studied. Forty-five placebo-controlled RCTs met the inclusion criteria. The placebo response ranged from 16.0 to 71.4% with a population-weighted average of 40.2%, 95% CI (35.9-44.4). Significant associations with lower placebo response rates were fulfillment of the Rome criteria for study entry (P=0.049) and an increased number of office visits (P=0.026). Placebo effects in IBS clinical trials measuring a global outcome are highly variable. Entry criteria and number of office visits are significant predictors of the placebo response. More stringent entry criteria and an increased number of office visits appear to independently decrease the placebo response.

Subject’s global assessment of satisfactory relief as a measure to assess treatment effect in clinical trials in irritable bowel syndrome (IBS)

Subject’s global assessment of satisfactory relief as a measure to assess treatment effect in clinical trials in irritable bowel syndrome (IBS)

Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

Rome I versus Rome II; Overlap in patients enrolled in tegaserod phase III clinical trials for irritable bowel syndrome (IBS)

Quality of Life in Patients with Irritable Bowel Syndrome Seen in Referral Centers Versus Primary Care: The Impact of Gender and Predominant Bowel Pattern

Background: Quality of life (QOL) is reduced in patients with irritable bowel syndrome (IBS) and little is known about differences in QOL in relation to referral status, gender and predominant bowel pattern in IBS patients. This study aimed to explore these relationships. Methods: 343 patients with IBS according to the Rome I criteria (251 females, 92 males) completed five different self-administered questionnaires to evaluate QOL. There were 119 patients with diarrhea-predominant IBS (IBS-D), 93 with constipationpredominant IBS (IBS-C) and 131 with alternating constipation and diarrhea (IBS-A). The study group comprised 209 hospital outpatients and 134 primary care patients. The questionnaires were mailed to the patients with an overall response rate of 88%. Results: QOL was reduced in hospital outpatients compared to primary care patients, but only in females. IBS subgroup (IBS-D), physical fatigue and general health independently predicted referral to a gastroenterologist. Females had lower QOL than males. No differences, except in severity of diarrhea and constipation, were observed between IBS subgroups. Perceived fatigue was related to well-being, psychological and gastrointestinal symptoms. Independent predictors for fatigue were depression, trait anxiety, general health and vitality, along with eating dysfunction and female sex. Conclusion: IBS female patients seen in referral centers versus primary care is a highly selected group with reduced QOL. QOL in IBS is affected by gender, but not by subgroup. Our findings have implications for the generalizability of results in IBS trials. Fatigue is a common symptom in IBS that correlates to general well-being and psychological and subjective gastrointestinal symptoms.

Validation of a global relief measure in two clinical trials of irritable bowel syndrome with tegaserod

Validation of a global relief measure in two clinical trials of irritable bowel syndrome with tegaserod

Irritable bowel syndrome clinical trial design: future needs

This article addresses a series of points that should be considered in the design of future clinical trials in irritable bowel syndrome (IBS). A precise, uncontroversial definition of the disorder and the affected patient is required that accurately describes the condition that practitioners recognize intuitively exists. Regarding patient source and selection, the principle should be applied that patients be recruited to trials from all sources to which an indication is intended. Because abdominal pain is the most central symptom of IBS, it should be used as the primary trial endpoint. Because there are currently no effective treatments, placebo-controlled trials pose no ethical problems. High placebo responses may equally well be the temporary spontaneous improvements that are characteristic of the condition. Clinical trials should be designed to meet specific aims of treatments: when taken as single doses to terminate an attack of pain; when taken over a brief period of time to speed resolution of a period of exacerbation of IBS; when taken after termination of a period of activity to prevent relapse; when taken regularly on a long-term basis to reduce the days on which a number of symptoms are experienced; when taken in form of discrete courses of treatment designed to achieve a pivotal change in the natural history of the condition.

Problems and challenges in the design of irritable bowel syndrome clinical trials: experience from published trials

The last two decades have seen many studies that are of inadequate design and power. This report focuses on what we have learned from the 25 randomized, controlled studies that included at least 30 patients during the period 1976–1998. The most important finding has been that the median placebo response was 47% (range, 0–84%), which is approximately three times the size of the difference between placebo and drug response, median 16% (range, −17–64%). This tells us the importance of reassurance and the powerful nonspecific therapeutic effects of entering patients into clinical trials in irritable bowel syndrome (IBS). Patients should be stratified according to the dominant symptoms that are relevant to the drug’s intended effect. A randomized, double-blind, controlled, parallel group study appears the most robust design. Minimizing the placebo response reduces the numbers needed to detect a significant difference. The optimum length of trial is probably >3 months, because the placebo effect takes approximately 12 weeks to start to recede. Dose titration should maximize the chance of detecting a benefit.

Entry criteria for drug trials of irritable bowel syndrome

This review explores a broad range of patient characteristics that might be considered when selecting patients for inclusion into drug trials for irritable bowel syndrome (IBS). These characteristics have been chosen according to the author’s perspective and a review of the literature based on a Medline search encompassing references to IBS (clinical, pharmacologic, and drug trials) from 1966 to 1998. The focus is to improve patient selection, which until now has concentrated predominantly on physical symptoms. Irritable bowel symptoms involve both physical and psychological domains in an inseparable way, the interaction profoundly affecting the physical manifestations of the condition, the patient’s interpretation of these physical changes, the ability of the patient to cope with these symptoms, the extent to which the patient feels the need to seek treatment, and the response to different types of treatment. Selection criteria need to take both physical and psychological domains into account. When defining the disorder for purposes of patient selection, a simple definition of long-standing abdominal pain and bloating associated with alternating diarrhea and constipation (after the exclusion of organic disease) may still be the most practical. The Manning and Rome criteria have been reasonably well validated, especially when the constellation of symptoms is used as a unit; however, their applicability to men and the elderly is not as well validated and deserves further attention. Other patient characteristics that may be useful in the future in deciding suitability for a trial, or predicting response, include symptom pattern, length of symptom history, whether the condition was triggered by enteric infection, whether a patient is in primary, secondary, or tertiary care, psychological characteristics, a history of physical or sexual abuse, and possibly visceral sensitivity testing or autonomic dysfunction. Different studies may be required for primary care and tertiary care patients, who may differ in their psychological characteristics. Studies should also include patients across the demographic spectrum who are likely to require treatment for this condition, including adolescents and the elderly. The type of drug being tested will also influence patient selection, depending on whether it is fast or slow acting, and its predominant pharmacologic effects and side effects. This has particular relevance in relation to the presence of diarrhea or constipation, how prominent the symptom of pain is, and whether the drug has psychotropic or anxiolytic effects. Because of the recognition that IBS patients compose a heterogeneous population, precise characterization of patients, and targeted drug therapies are likely to lead to better therapeutic results. Further attention also needs to be paid to the type of drug under investigation, in relation to these different patient characteristics.

Experience with anxiety and depression treatment studies: implications for designing irritable bowel syndrome clinical trials

This report highlights various considerations regarding the potential effects of concurrent psychiatric conditions and a history of abuse in patient volunteers for clinical trials in irritable bowel syndrome (IBS). Even though many studies have used psychological rating scales to assess personality and psychological traits of patients with IBS, the prevalence of the different psychiatric diagnoses (i.e., categorical assessment) in patients with IBS has only recently been assessed systematically. Recent studies of treatment-seeking patients have indicated that the majority of individuals (50% to 90%) who seek treatment for IBS have a lifetime history or currently have one or more common psychiatric conditions: major depressive disorder, generalized anxiety disorder, panic disorder, social phobia, somatization disorder, and posttraumatic stress disorder. Traditional clinical wisdom is that the presence of a psychiatric disorder increases the likelihood that an IBS patient will seek treatment. However, recent data suggest that IBS and psychiatric disorders are associated regardless of treatment-seeking status. Patients with psychiatric disorders should be included in clinical IBS studies, because this reflects the actual patient population. Extrapolating from the psychiatric literature, inclusion of patients with IBS with mild to moderate anxiety or depression is warranted.

Inclusion and exclusion criteria of importance in irritable bowel syndrome trials

Although numerous diseases may mimic or be confused with irritable bowel syndrome (IBS), a detailed and precise clinical history and a normal clinical examination usually lead to an accurate diagnosis of IBS. The presence of symptom criteria and the absence of warning signs must be established. Before entering a clinical trial, several routine tests are generally required: total blood count, erythrocyte sedimentation rate, biochemistry screen, stool culture and examination for occult blood, ova, and parasites, and a recent (<2 years) normal flexible sigmoidoscopy or colonoscopy with biopsy. Blood and stool tests are not necessary for the diagnosis of IBS but are important in the framework of controlled trials. Esophagogastroduodenoscopy, abdominal ultrasonography, and malabsorption tests are needed only in patients with atypical IBS or for phase II trials in certain subgroups of patients. Chronic diseases, drugs, and toxic agents that may mimic IBS symptoms or exacerbate the disorder must be excluded. Errors in patient inclusion will be minimized if the duration and severity of IBS symptoms before inclusion is sufficient and will have little effect on the result of the trial if the new drug is really effective and the study well randomized with a correct calculation of sample size.

Development of a questionnaire to measure quality of life in patients with irritable bowel syndrome.

To develop a questionnaire for measuring health-related quality of life (HRQL) in patients with Irritable Bowel Syndrome (IBS). We surveyed the existing literature, and interviewed patients and clinicians, to develop a list of 182 potential problems for IBS patients. One hundred patients with IBS completed a questionnaire in which they told us whether each of the 182 items was a problem for them, and if so the magnitude of their importance in their lives. Patients identified four major problem areas: bowel symptoms, fatigue, activity limitations, and emotional dysfunction. On the basis of these findings, we constructed a 26-item questionnaire which, in pre-testing, 16 patients found clear and easy to complete. We have developed a questionnaire that measures HRQL in IBS patients and is suitable for use as an outcome measure in clinical trials in IBS.

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 selec...

Conference Report

There are several clinical problems that frequently present to general practice which are not of sufficient severity to warrant further investigation. These disorders are usually managed effectively by the general practitioner (GP) with routine examination and simple advice or treatment. Patients who repeatedly visit their GPs because of failure to respond to such measures are those most likely to be referred to specialists for a further opinion and possibly more extensive evaluation. As much research is still conducted in specialist centres, it is usually undertaken on this unrepresentative sample of patients. Conclusions and guidelines derived from this type of work are then transferred back to primary care where they may not be entirely applicable. Irritable bowel syndrome (IBS) is a typical example of such a disorder and since research in general practice is becoming much more widespread, now is a good time for this condition to be more fully evaluated in the prmary care setting. It was against this background that representatives of European general practice and gastroenterology met in London to discuss the feasibility of undertaking primary care therapeutic trials in IBS. This paper will discuss some of the differences between GP and hospital IBS patients, the need for research in primary care and the problems associated with undrtaking such studies.