• irritable bowel syndrome
• tegaserod
• Asia-Pacific
• double blind study

Until recently, there existed little evidence that any therapy was effective for irritable bowel syndrome (IBS). The quality of clinical trials was poor,^1,2 and no systematic review^3,4 can redeem faulty data.⁵ Mindful of this, pharmaceutical companies now employ modern clinical trial principles to test IBS drugs. The latest of these efforts is an Asia-Pacific randomised controlled trial of tegaserod by Kellow et al, described in this issue of Gut⁶ [see page 671].⁶ To judge how well tegaserod matches the needs of IBS patients we must examine the trial methods, results, and conclusions, and divine what is missing from the reports.

The Asia-Pacific study is similar to Western IBS trials of tegaserod.^7,8 These represent substantial improvements in trial methodology. The entered subjects had criteria defined IBS and most had a “non-diarrhoea” bowel habit suitable to the drug’s effects. Recruitment was sufficient to show definitive results, and subjects were double blinded and randomly allocated. A primary global outcome was selected with appropriate secondary measures, and the analysis was “intention to treat”. Primary outcome differences were consistently significant at the pre-decided end point, and over 12 weeks. Tegaserod appears safe (sine qua non for IBS), and post-marketing surveillance should detect unexpected adverse effects.

The Kellow study achieved greater therapeutic gain (absolute benefit increase) than prior tegaserod studies (21% v 11.8%⁷ and 5.7%⁸) but with several methodological differences. Whereas the subjects in the Western trials were 98% Caucasian and mostly English speaking, 84% of the Asia-Pacific subjects were Asian whose language is unreported. The Western trials entered patients with Rome I IBS criteria plus two of three constipation criteria. The Asia-Pacific trial used Rome II criteria excluding only those with predominant diarrhoea.

In the West, the primary outcome measure was the subject’s global assessment (SGA) of relief recorded weekly on a five point scale with predetermined responder definition. The Asia-Pacific measure was “yes” or “no” to “satisfactory relief of symptoms of IBS”. In previous trials, tegaserod produced relief earlier than placebo, but the therapeutic gain lessened over 12 weeks. Therefore, the Asia-Pacific investigators chose the first rather than the last four weeks as the primary end point. Earlier trials compared responders as their primary outcome, while the Asia-Pacific study compared responses (“responders” a secondary outcome). These differences help explain the greater therapeutic gain in the Asia-Pacific trial.

The methods and data described in the tegaserod reports are vastly superior to previous trials of available drugs (alosetron aside), and the results are consistent. Nevertheless, some facts and interpretations are missing. In the Asia-Pacific trial, the “prokinetic” properties of tegaserod are demonstrated by diarrhoea (10% v 3% for placebo), less laxative consumption (23.2% v 34.1%), and more frequent, and looser stools. In all three trials these effects are immediate. While participants were double blinded initially, no exit tests for blinding are described. Did some subjects suspect they were on tegaserod because of its prokinetic effects? The outcomes are subjective, so results could be biased if some patients or investigators realised who received tegaserod.

The “SGA of relief” is attractive because it embraces the multifaceted symptoms of IBS and identifies satisfied patients. However, there is a pitfall. Let us suppose that the only effect of tegaserod is prokinetic (without the believed reduction in visceral hypersensitivity). Increased defecation in the mainly constipated patients could provoke a “yes” response to the SGA. The tendency of other secondary outcome measures to improve is reassuring, but in the Kellow study discomfort, pain, and bloating improvements were insignificant. Indeed, diary data indicate “no bowel movements” and “hard or lumpy stools” as the only secondary measures significantly improved in either the first or last 28 days (see table 3). Could a suitable laxative more cheaply achieve the same result? Could relief of constipation improve discomfort, bloating, or even pain? Without trials comparing tegaserod with laxatives, we cannot know.

Over 80% of subjects are female and one trial omitted men.⁸ Data are insufficient to evaluate the benefits of tegaserod in men, but the present study shows a non-significant 10% therapeutic gain in the first four weeks and none over 12 weeks. Why should only women respond? Perhaps there are hormonal and psychological explanations,⁹ and bloating (part of global outcome) is uncommon in men.¹⁰

The authors of all three reports regret the “relatively high placebo response”, implying that if it were lower a greater therapeutic gain might be achieved. This is likely fallacious. The effects of a treatment depend on its physiological effects plus natural history of the condition being treated plus “placebo effect” (that is, those benefits of healer-patient interaction).^5,11,12 These act in concert to make patients feel better. The placebo response in the tegaserod studies are similar in other IBS, dyspepsia, peptic ulcer, and ulcerative colitis trials.^12,13 The increasing placebo response over the 12 week treatment can be attributed to the care, enthusiasm, and education provided by the protocol, and the tendency of IBS symptoms to improve.¹² Placebo responses are allies that should be recruited with all treatments.

Missing from the discussion is guidance on how to use this newly available drug (not yet in Europe). It is not a perfect match for IBS. The data establish the efficacy of tegaserod for women with Rome IBS without diarrhoea. However, for many, IBS is a fluctuating lifetime experience beginning in the teens. Do they all need tegaserod? If so, should they take it indefinitely? Would tegaserod work best for short troublesome periods or “as needed”? What guides its use through IBS patients’ inevitable alterations in bowel habit? What about using tegaserod in other functional disorders such as dyspepsia or functional constipation? Current data provide no answers.

While IBS clinical trials may now be state of the art, there is room for improvement. Future designs should ensure blinding or allow for its breach. Designers must improve treatment protocols and outcome measures to more accurately match the needs of IBS patients. Gender differences and IBS subtypes require confirmation. Pathogenesis is unknown and therefore cure is unlikely in the short term. Meanwhile, scientists and clinicians should strive to improve IBS palliation. Drugs affecting gut motility should be compared with cheaper antidiarrhoeals and laxatives. Placebo effects should be seen as complimentary, not the enemies of science and drug validation.

What can practising doctors make of this? Recent IBS trials represent a breakthrough in IBS trial methodology, but tegaserod provides palliation not cure. Most women with IBS and constipation do well with good doctor-patient relationships; confident diagnosis, explanation, optimistic yet realistic prognosis, management of psychological comorbidity, and diet and lifestyle advice.^11,12 For the unimproved with impaired enjoyment of life, tegaserod offers hope and help. Available information suggests that treatments should be short—for example, 2–4 weeks—continuing only if constipated IBS symptoms persist and improvement justifies the cost. What is yet unjustified is the use of tegaserod indefinitely, in men, in IBS with diarrhoea, or other diagnoses. The tegaserod trials are progress but for IBS no therapy is perfect.

Conflict of interest: Over my 30 year study of IBS I served as an advisor and teacher about IBS for several pharmaceutical companies including in the last year, Novartis, Glaxo Smith Kline, Merck (Germany), Shering Plough, and Procter and Gamble.