A 2-week course of rifaximin was associated with adequate relief of irritable bowel syndrome symptoms for the first 4 weeks after completion of therapy in 41% of patients who had IBS without constipation.
The results of two identical phase III placebo-controlled studies, TARGET 1 and TARGET 2, were similar overall, Dr. Mark Pimentel and his colleagues wrote in the Jan. 6 issue of the New England Journal of Medicine (2011;364:22-32).
TARGET 1 found that 41% of those taking rifaximin reported adequate relief of their global IBS symptoms, compared with 31% of those taking placebo (P = .01), for at least 2 of the first 4 weeks after treatment ended. In TARGET 2, those numbers were 41% vs. 32% (P = .03), and for the two studies combined the results were also 41% vs. 32%, respectively (P less than .001).
Rifaximin, a poorly absorbed broad-spectrum antibiotic, may work by controlling bacterial overgrowth in the gut, wrote Dr. Pimentel of the Cedars–Sinai Medical Center, Los Angeles, and his colleagues. However, the authors explained, "Some patients in both of our studies did not have a response to treatment, a finding that is consistent with the results of other placebo-controlled clinical trials involving patients with IBS and that may reflect differences in the underlying cause of the symptoms."
Both studies were funded by Salix Pharmaceuticals, the drug’s manufacturer. They included a total of 1,260 patients (623 in TARGET 1 and 637 in TARGET 2). All patients were randomized to 14 days of either placebo or 550 mg rifaximin three times daily and were followed weekly for 10 additional weeks. Study retention was high, with 90% completing the entire trial. Last-results carried forward were used in a secondary analysis.
The patients’ average age was 46 years in each group. Overall, most patients (about 72%) were female, and 91% were white. All had IBS without constipation, with an average duration of 11-12 years.
Patients eligible for the study rated their IBS symptoms of abdominal pain and bloating as a 2-4.5 on a 7-point Likert scale (where 0 = not at all, and 6 = a very great deal). Most patients (82%) reported daily stool urgency.
The primary end point was adequate relief of global IBS symptoms, which patients answered with "yes" or "no." The authors prospectively determined the threshold of "adequate relief" as a score of 0 or 1 for at least 50% of days in a given week and 1 or 2 for 100% of the days in a given week. Additionally, patients were asked to rate relief of bloating, abdominal pain and discomfort, and daily stool consistency.
Overall, significantly more patients in the active group than the placebo group met the primary end point (41% vs. 32%). The secondary analysis with last observation carried forward yielded similar results.
In the two studies combined, significantly more patients in the active group than the placebo group reported adequate relief of bloating for at least 2 of the first 4 weeks after treatment (40% vs. 30%; P less than .001). For the composite end point of abdominal pain or discomfort and loose or watery stools during this time period, significantly more patients treated with rifaximin had relief, compared with placebo-group patients (TARGET 1: 47% vs. 39%, P = .04; TARGET 2: 47% vs. 36%, P = .008).
In an analysis of durability of response based on a weekly assessment, "more patients in the rifaximin group than in the placebo group in both studies had adequate relief of global IBS symptoms within the first month, with continued relief during the first 2 months and during all 3 months in both studies," the authors wrote, noting that the difference was significant at P less than .001 for both studies combined, for relief during all 3 months.
The authors provided a supplementary appendix containing graphs showing that the percentage of patients with adequate relief of global IBS symptoms declined in both groups, in both studies, during the 10 weeks after treatment.
Two patients in the rifaximin group and five in the placebo group had serious adverse events. The incidence of infections was similar in the two groups. There were no cases of ischemic colitis and no deaths.
Regarding the mechanism of action, the authors noted several possible pathways. Besides altering the balance of the gut flora, the drug might also decrease gas associated with bacterial activity, reduce local inflammatory response to bacteria, or alter both the bacteria and host response.
"Whatever the final pathway, the durable effects suggest that rifaximin is affecting an underlying cause of IBS that is linked to an alteration in the intestinal microbiota," they said.