Brooks D. Cash, Michael Epstein, Syed M. Shah
Background: There are high placebo response rates in IBS clinical trials. Recently, more restrictive outcome measures have been developed for IBS trials to distinguish between active treatment response and placebo response. However, a stringent responder endpoint may not accurately convey the degree of clinical improvement. The IBS Reduction Evaluation and Safety Trial (IBSREST) showed that PO-SST, a novel formulation of peppermint oil using solid-state microspheres to target the small intestine, was an effective IBS therapy at 24 hours, with improved efficacy at 4 weeks. In this post-hoc analysis of IBSREST data, we sought to determine if there was a meaningful response difference between “any improvement” and the high hurdle of “40% improvement” with PO-SST versus placebo.
Methods: IBSREST subjects met Rome III criteria for IBS-M or IBS-D, had average daily IBS related abdominal pain of ≥ 4 on a 0-10 scale, and a TISS of ≥ 2 on a 0-4 scale. Subjects were randomly allocated to receive PO-SST 180 mg TID or placebo for 4 weeks. Primary analysis was based on the TISS and a secondary analysis evaluated change from baseline in abdominal pain. Supportive analyses were performed classifying subjects as responders if they experienced ≥ 40% improvement in TISS or abdominal pain. Results: Twenty-four hours after the first dose, 14% receiving PO-SST were responders with ≥ 40% improvement in TISS vs. 0% receiving placebo (P=0.017), while 77% receiving PO-SST were responders with “any improvement” vs. 62% receiving placebo (P=0.17; Figure 1). At 24 hours, the response rate for abdominal pain was 23% in patients receiving PO-SST for a ≥ 40% improvement vs. 0% with placebo (P=0.002), while 60% receiving PO-SST had “any improvement” vs. 51% receiving placebo (P=0.46). After 4 weeks of treatment, 44% receiving PO-SST were responders with ≥ 40% improvement in TISS vs. 30% receiving placebo (P=0.21), while 94% receiving PO-SST were responders with “any improvement” vs. 81% receiving placebo (P=0.099; Figure 2). At 4 weeks, 47% receiving PO-SST and 27% receiving placebo were responders with ≥ 40% improvement in abdominal pain (P=0.081), while for “any improvement” response rates for PO-SST were 91% vs. 65% for placebo (P=0.008).
Conclusion: In patients with IBS-M and IBS-D, a numerically higher percentage of patients responded, in all measurements, to PO-SST vs. placebo and some of these reached statistical significance. The difference in response rates at the stringent “40% improvement” threshold tended to be pronounced within 24 hours for global IBS symptoms and abdominal pain while differences in the more general outcome of “any improvement” were retained at 4 weeks for abdominal pain, supporting a consistent effect on abdominal pain with PO-SST in IBS-M and -D patients.
