Original ArticlesProblems and challenges in the design of irritable bowel syndrome clinical trials: experience from published trials
Section snippets
What have we learned from 1976 to 1998?
This section is based on an analysis of 25 randomized controlled trials published during this period that have included >30 patients and excludes many more with either smaller numbers or inadequate design. These 25 trials studied the efficacy of antispasmodics (13), bran (4), antidepressants (3), loperamide (3), cisapride (2), and isphagula (1).
Patient definition
Early studies used diagnostic criteria for IBS that varied from study to study. Whereas most required that patients should have normal barium studies and in some cases blood tests, few specified symptoms or their frequency. Although variable bowel habit was usually required, this was not quantified. More importantly, pain was not always included in the definition, which was effectively one of exclusion. In 1990 a working party produced the “Rome criteria,”2 which defined the syndrome more
Specific endpoints
Global assessments of severity relate poorly to specific symptoms and more to quality-of-life issues, such as how symptoms interfere with patients’ lives.7 Using global response as an endpoint has a logic, because this is what the patients want to improve, and may be more informative for evaluating centrally acting drugs than specific changes in bowel habit. However, global response measures miss some specific effects. Only a panacea or a centrally acting psychotropic drug would treat all
Placebo response
As already mentioned, the placebo effect is much larger than any drug effect, so we need to understand and control for this or else it will overshadow any specific benefit of the drug. Several studies have documented in detail the placebo-related decrease in anxiety, which occurs steadily from trial entry for the next 6 to 8 weeks.15 Others have documented the decrease in anxiety after being told an investigation is normal.17 For patients with low initial anxiety, there is a substantial and
Effects of lengthening trial
On current evidence, as presented above, the ideal of a low placebo response (<20%) may be achieved by running the trial for ≥3 months. Such a trial may require significantly fewer patients, but would it be easier to conduct? There is not much evidence on this point.
Minimal symptoms
The practice of excluding patients with minimal symptoms makes sense, because in clinical practice such patients should not receive drug therapy. Any trial using a large proportion of mild cases would be considered to have studied the wrong patient group. Furthermore, one would predict that the placebo response would be high, and thus the numbers required for a significant result would be very large. However, the threshold for entry needs to be realistic. Previous studies using a daily
Effect of placebo response on crossover design
Patients who receive active treatment in the first part of the study may well respond differently if a placebo response is still developing. Crossover designs reduce the numbers of patients needed to be recruited and are potentially more powerful, but are difficult to interpret if there is a big order effect. It is quite common to find a carry-over effect with, for example, laxatives, with which the improvement in constipation continues for some time. This means that an active drug taken first
Dose titration
The idea of adjusting the dose according to the patient’s response makes a great deal of sense, because this allows one to take into account different body weights and drug metabolism. It also allows one to use the largest dose tolerable, thus ensuring an optimal balance between therapeutic and associated but undesirable effects. Some studies have used this approach. Thus, Cann et al9 allowed patients to increase or decrease the dose of loperamide or placebo according to the response. They
Side effects
It is important that these are systematically reported, both because side effects may limit subsequent use of the treatment outside a clinical trial and also because they effectively unblind the trial, giving rise to the risk of bias in both the patient and investigator. One study, using the tricyclic antidepressant desimipramine, used atropine as a control, in addition to placebo, because the dry-mouth side effect of desipramine could not be controlled in any other way.29 The atropine had no
Documenting recruitment and drop out
Keeping a record of what proportion of patients encountered in clinical practice were considered suitable for recruitment and how many dropped out has been done in very few studies, which are written as if this never occurred. This is vital, because most authors would like to believe that the results of their trial will be applicable to the entire population of patients seen with IBS. If, however, only a select group of patients agree to enter, then this may not be valid. Recording the
Statistics and power
The use of appropriate statistics and ensuring that enough subjects are included to ensure adequate power to answer definitively the question under study is accepted by all. Many studies in the literature used far too few patients to show an effect unless this was extremely large. A recent review of published studies of smooth muscle relaxants16 reported the median number of patients studied to be 29 (range, 8–178) with a mean proportion of patients improving on the drug of 0.35 and on placebo
Conclusions
The large placebo response and relative ineffectiveness of therapy tell us a lot about IBS. Previous studies have, in retrospect, been poorly designed and analyzed. Patients should be stratified according to their dominant symptoms, because many drugs with specific effects are likely to benefit one group specifically and may actually aggravate some patients’ symptoms. Trials with newer drugs acting more on perception or coping behavior may require stratification by psychological parameters
References (30)
Controlled treatment trials in the irritable bowel syndromea critique
Gastroenterology
(1988)- et al.
Controlled study of psychotherapy in irritable bowel syndrome
Lancet
(1983) - et al.
Identification of sub-groups of functional gastrointestinal disorders
Gastroenterol Int
(1990) - et al.
Double-blind study of the effect of cisapride on constipation and abdominal discomfort as components of the irritable bowel syndrome
Aliment Pharmacol Ther
(1997) - et al.
The irritable colon syndrome
Q J Med
(1962) - et al.
Effects of acute psychologic stress on small-intestinal motility in health and the irritable bowel syndrome
Scand J Gastroenterol
(1992) - et al.
Steroid hormone abnormalities in women with severe idiopathic constipation
Gut
(1991) - et al.
Patient-perceived severity of irritable bowel syndrome in relation to symptoms, health resource utilization and quality of life
Aliment Pharmacol Ther
(1997) Loperamide treatment of the irritable bowel syndrome
Scand J Gastroenterol
(1987)- et al.
Role of loperamide and placebo in management of irritable bowel syndrome (IBS)
Dig Dis Sci
(1984)