Once-daily ramosetron improved stool consistency in male patients with diarrhea-predominant irritable bowel syndrome, Dr. Shin Fukudo and colleagues reported in the June issue of Clinical Gastroenterology and Hepatology 2014 [doi:10.1016/j.cgh.2013.11.024].
Indeed, compared with other 5-hydroxytryptamine3 (5-HT3) agonists in its class, the "high selectivity, clear efficacy, and lower incidence of serious adverse events suggest that ramosetron is the most promising therapeutic agent for IBS-D [irritable bowel syndrome–diarrhea subtype]," Dr. Fukudo and associates wrote.
In the current study, which was funded by the drug’s maker, Astellas Pharma, Dr. Fukudo of Tohoku University Graduate School of Medicine, in Sendai, Japan, looked at male patients aged 20-64 years diagnosed with IBS-D according to Rome III criteria.
To begin, subjects were monitored for 1 week to gather baseline assessments of severity of abdominal pain/discomfort, using a five-point ordinate scale, as well as stool consistency – the primary endpoint of the study – using the Bristol Stool Form Scale (BSFS).
For inclusion in the analysis, patients had to demonstrate mean abdominal pain/discomfort scores of at least 0.7 during the baseline period, have no type 1 or 2 stool form, and have an overall mean score of greater than 5 on the BSFS.
Patients were then randomized to a 12-week regimen of either ramosetron 5 mcg daily before breakfast or placebo and began recording their IBS symptoms daily on paper diary cards as well as in a voice-activated electronic database system.
Overall, 148 placebo patients and 147 ramosetron-treated patients were included in the analysis.
Looking at the primary endpoint, Dr. Fukudo found that in the first month, 50.3% of patients in the ramosetron group reported improvement in stool consistency (95% confidence interval, 42.0%-58.7%) versus 19.6% among placebo patients (95% CI, 13.5%-26.9%) (P less than 0.001).
That trend held for the remainder of the study, with a significantly greater portion of ramosetron patients consistently logging gains in stool consistency from month to month.
Similarly, the ramosetron group also recorded changes in the severity of abdominal pain/discomfort week from baseline, with a decrease in severity of 0.78, compared with mean weekly reductions of 0.60 among placebo patients.
The difference between groups, however, was only significant at week 5, with a mean 0.70 decrease in symptoms over the previous week, compared with 0.48 for placebo (P = .012).
Safety profiles, meanwhile, were similar for both drugs: adverse events occurred in 46.9% and 51.7% of ramosetron and placebo patients, respectively, with constipation occurring in 3.4% of treatment patients versus 0.7% of placebo patients, a nonsignificant difference.
Moreover, "All episodes of constipation and hard stools in the ramosetron group, assumed to be caused by the pharmacologic actions of ramosetron, were classified as mild and resolved early without using rescue drugs."
According to the researchers, the efficacy of ramosetron likely stems from the "crucial role" that 5-hydroxytryptamine plays in IBS-D pathophysiology.
"IBS-D patients have exaggerated colonic motility in response to colorectal distention," they wrote.
Since the distention-induced peristaltic reflex is mediated by 5-HT, and since abnormal neurotransmission of 5-HT via the 5-HT3 receptor has been reported in IBS-diarrhea patients, "Use of a 5-HT3 antagonist for IBS-D patients is a logical consequence."
In addition to the disclosure that the study was funded by Astellas Pharma, Dr. Fukudo also disclosed working as a contracted consultant to the company, along with a coinvestigator; the three remaining authors are Astellas employees.