Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by recurrent symptoms of pain, bloating, and altered intestinal function in the absence of structural, inflammatory, or biochemical abnormalities.
IBS often does not respond to current treatment options, including diet and lifestyle changes, fiber supplements, psychological therapy, and pharmacotherapy. Given the limitations of available therapies, there is an unmet medical need for new therapeutic approaches.
Patients with IBS may have alterations in the intestinal microbiota. Although some have improved with neomycin therapy, it has marginal efficacy and limiting side effects. The use of systemic antibiotics has been reported with mixed results.
Rifaximin is a broad-spectrum, non-systemic, oral antibiotic targeting the intestine with a low risk of bacterial resistance.
It has shown effectiveness in small studies on IBS. We present the results of two large-scale, identically designed, multicenter studies, TARGET 1 and 2, of 3 months duration that examined the relief of IBS symptoms after a 2-week course of rifaximin.
| Results |
> Patients. 1260 patients who had IBS without constipation (623 in TARGET 1 and 637 in TARGET 2) were enrolled and randomized to one of 179 investigational sites in the United States and Canada. The studies were conducted in parallel from June 2008 to August 2009. In TARGET 1, all randomized patients took at least one dose of study drug.
In TARGET 2, two patients (one in each group) were randomized, but did not receive study drug. Thus, 1258 patients received at least one dose of rifaximin and were included in the modified intention-to-treat population. More than 90% of patients completed the 12-week study.
Baseline patient characteristics were similar in both studies and in all treatment groups. The drug adherence rate, defined as the use of at least 70% of dispensed tablets, was at least 97% in both studies.
> Efficacy during the primary evaluation (weeks 3 to 6). Significantly more patients in the rifaximin group than in the placebo group met the primary endpoint of adequate relief of global IBS symptoms for at least 2 of the first 4 weeks post-treatment (40.8% vs. 31.2% in TARGET 1; 40.6% vs. 32.2% in TARGET 2; 40.7% vs. 31.7% in the combined studies).
Based on daily assessments of IBS symptoms on a 7-point scale, relief was significantly greater in the rifaximin group than in placebo (42.7% vs. 30.6%, in TARGET 1; 37, 8% vs. 28.4% in TARGET 2; 40.2% vs. 29.5% in the two studies combined).
Significantly more patients in the rifaximin group than in the placebo group met the secondary endpoint, adequate relief of IBS-related bloating, for at least 2 of the first 4 weeks post-treatment (39.5% vs. 28.7%). % in TARGET 1; 41.0% VS. 31.9% in TARGET 2; 40.2% vs. 30.3% in the two studies combined).
Based on daily assessments according to the 7-point scale, a significantly higher proportion of patients in the rifaximin group than in the placebo group had relief of distension (39.2% vs. 32.5% in TARGET 1; 43, 5% vs. 30.9% in TARGET 2; 41.3% vs. 31.7% in the two studies combined).
A significantly higher proportion of patients in the rifaximin group than in placebo had relief from IBS-related abdominal pain and discomfort during this period (44.3% vs. 36.3% in TARGET 1; 42.9% vs. . 34.4% in TARGET 2).
Assessing the composite endpoint of abdominal pain or discomfort and loose or watery stools, significantly more patients in the rifaximin group than in placebo had symptom relief (46.6% vs. 38.5% in TARGET 1 ; 46.7% VS. 36.3% in TARGET 2), and a significantly greater proportion of patients in the rifaximin group improved in relation to the individual components.
> Efficacy throughout the study period (months 1 to 3). In analyzes of monthly response assessed based on weekly assessments, 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 for the first 2 months. months and during the 3 months.
Regarding IBS-related bloating, in TARGET 1, significantly more patients in the rifaximin group had adequate relief in the first month, with continued relief for the first 2 months, but there were no significant differences between groups for 3 months ; In TARGET 2, significant benefits of rifaximin were observed over 3 months.
Monthly response analyzes evaluated based on daily assessments also support a durable response to rifaximin in patients with IBS over the course of 3 months. Patients treated with rifaximin vs. placebo, had adequate relief of overall IBS-related symptoms and bloating over the entire 3 months of the study.
With respect to abdominal pain and discomfort, significantly more patients in the rifaximin group than in the placebo group had relief for the entire 3 months. Analysis of the monthly response based on the evaluation of the composite endpoint of abdominal pain and stool consistency also showed a significant benefit with rifaximin vs. placebo.
The mean improvement from baseline in daily symptom scores (global symptoms, bloating, abdominal pain or discomfort, stool consistency, and percentage of days with urgency to defecate) was greater for patients receiving rifaximin vs. placebo.
Patient response regarding adequate relief of IBS-related global symptoms and bloating was consistent with response regarding other IBS-related assessments. Additionally, patients who had adequate relief of global symptoms and bloating had greater improvements in daily symptom severity scores than patients who did not have adequate relief, regardless of study group, during each week in each study.
The validity of using global IBS symptom assessments to measure changes in IBS symptoms was tested by examining the correlation between these measures and changes in daily severity and bowel function scores; The results supported the validity and usefulness of the primary endpoint. Evidence of convergent validity was observed between adequate weekly relief of global IBS symptoms and measures of daily symptom severity and bowel function.
> Security. The safety profile of rifaximin was similar to that of placebo. Serious adverse events were recorded in 10 patients in the rifaximin treatment group and in 15 patients in the placebo group. No deaths or cases of diarrhea or ischemic colitis due to Clostridium difficile were reported.
| Discussion |
Treating IBS is important because the symptoms cause a substantial deterioration in health-related quality of life, with increased use of healthcare resources and reduced work productivity. These two phase 3 studies showed that a short treatment with rifaximin leads to sustained improvement of IBS symptoms without constipation in a subgroup of patients.
The antibiotic effect of rifaximin is the presumed mechanism of its sustained beneficial effect in patients with IBS. Response to antibiotic therapy in patients with IBS has been shown to correlate with normalization of hydrogen and lactulose breath test results.
However, there is debate about which antibiotic-related effect is more important. Based on the evidence, there are three reasonable explanations: rifaximin affects intestinal bacteria and reduces bacterial products that negatively affect the host, the effect on intestinal flora reduces the participation of bacteria in the local mucosa, as well as the immune response. of the host, or the antibiotic alters both the bacteria and the host response.
Whatever the final route, the long-lasting effects suggest that rifaximin affects an underlying cause of IBS linked to alteration of the gut microbiota. Some patients in these two studies had no response to treatment, a finding consistent with the results of other placebo-controlled clinical trials in patients with IBS and which may reflect differences in the underlying cause of symptoms.
Similar percentages of patients in the rifaximin group and the placebo group had adverse events. The incidence of infections was similar in the two groups, and there were no cases of diarrhea or ischemic colitis associated with C. difficile.
| In summary , the results of these two phase 3 studies demonstrated that treatment with rifaximin at a dose of 550 mg three times a day for 14 days provided better relief of IBS symptoms than placebo up to 10 weeks after completing therapy. . |
