Objective
Our previous pilot study showed that treatment with the histamine 1 receptor antagonist ebastine improved symptoms in patients with irritable bowel syndrome (IBS). To further validate these findings, we designed a phase IIb placebo-controlled randomized multicentre clinical trial evaluating the effect of a 12-week ebastine treatment in non-constipated IBS.
Methods
202 patients (mean age 32±11 years, 68% female) fulfilling the Rome III criteria were randomly assigned to receive 20mg ebastine or placebo once daily for 12 weeks, of which 177 completed the study. Subjects scored global symptom relief (GSR, 6-point Likert scale, weekly), abdominal pain (AP, VAS scale, daily) and number of loose stools (type 6-7 bristol stool scale, daily). A subject is considered a weekly responder for GSR if total or obvious relief is experienced and a responder for AP if the weekly average pain score is reduced by at least 30% versus baseline. Primary endpoints according to FDA and EMA guidelines: weekly responders for GSR and AP combined (GSR+AP, FDA), and for GSR and AP separately (EMA), for at least 6 out of 12 treatment weeks. Secondary endpoints and post-hoc efficacy outcomes include the effect on stool consistency for patients with diarrhea-predominant IBS (IBS-D), and the proportion of weekly GSR+AP responders for 3 of the last 6 treatment weeks.
Results
Treatment with ebastine resulted in significantly more responders (12%) for GSR+AP compared to placebo (4%, p=0.047, primary FDA endpoint) while the proportion of responders for GSR and AP separately was higher, albeit not statistically significant (placebo vs ebastine, GSR: 7% vs 15%, p=0.072; AP: 25% vs 37%, p=0.081, primary EMA endpoints). Ebastine increased the proportion of weekly responders from week 6 onwards (w7-8: p<0.05). Analysis of the responder rate during the last 6 weeks confirmed the superiority of ebastine compared to placebo: GSR+AP, 8% vs 19%, p=0.04; GSR, 13% vs 20%, p=0.17; AP, 34% vs 49%, p=0.04 (placebo vs ebastine). Moreover, ebastine had a significantly greater effect on the decrease in abdominal pain during the 12-week treatment period compared to placebo (p=0.037). Stool consistency did not significantly differ between placebo (n=68) and ebastine (n=64) in IBS-D patients.
Conclusions
Our study shows that a 12-week treatment with 20 mg ebastine is superior to placebo and should be further evaluated as novel treatment for non-constipated IBS.

David Hirsch

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