Comments on tegaserod trial on irritable bowel syndrome.

TO THE EDITOR: Irritable bowel syndrome (IBS) remains to be a challenge for the gastroenterologist, due to its high prevalence and impacts on poor quality of life (QOL) with unsatisfactory pharmacological treatments. Most of the current treatment modalities for IBS have been directed at symptom relief rather than pathophysiology of the condition, which is heterogenous and poorly understood.1 I read the recent articles by Kim et al.2 about the tegaserod effects on IBS with great interest. The efficacy and safety of tegaserod have been demonstrated by several large randomized controlled trials.3,4 However, tegaserod was taken off the market by a high chance of having a myocardial infarction, stroke or angina.5

Kim et al.2 showed the efficacy of 5-hydroxytryptamine 4 (5-HT4) agonist in Korean women with IBS with constipation. In this study, tegaserod showed the relief of overall IBS symptoms such as abdominal pain/discomfort, number of bowel movements and stool consistency. They used the composite score of symptom frequency and severity as an endpoint in treatment of IBS. The previously published pharmaceutical trial for IBS have used "adequate relief of abdominal pain and discomfort" or "satisfactory relief of IBS symptoms" as their primary outcome measure which led to approvals for alosetron and tegaserod by the Food and Drug Administration (FDA).6 An alternative method for defining a responder in an IBS treatment trial is to ask patients to report the frequency and severity of all IBS symptoms. Kim et al.2 showed the adequate symptom relief and good correlation between symptom composite score and IBS-QOL, which might show the usefulness of Korean IBS-QOL in IBS therapeutic trial. However, it is not clear whether reduction of sum-score of 22.5/96 (23.5%) was enough to define a responder. They conducted this trial as open arm without placebo control. The FDA have recommended investigators to provide rules, a priori, which allow classification of each participant as a responder or non-responder for the primary outcome.7 The secondary outcome is used to strengthen the results by showing concordance between individual symptoms and the primary outcome measure, addressing the mechanism of the intervention, and assessing the safety.6 Kim et al.2 also proposed QOL to be included as a therapeutic outcome.

Recently, there are many pharmaceutical trials including the next generation 5-HT agonists, such as Prucalopride, TD-5108, and ATI-7505 in IBS.8 I am hoping for the present study to strengthen the pharmaceutical research in IBS. The primary outcome variables provide the basis for judging the success or failure of an intervention, therefore, further studies on the outcome measurements in IBS drug trials, which can properly quantify drug responses, are warranted.