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Chapter 10 242 Peppermint oil is a promising low-cost drug for IBS, but evidence from high quality randomized controlled trials was still limited. We investigated its efficacy in a well- designed trial according to FDA and European Medicines Agency (EMA) guidelines ( chapter 7 ). In addition to the conventional enteric-coated peppermint oil with small- intestinal release, a newly developed ileocolonic release peppermint oil ( chapter 6 ) was studied. We hypothesized that both formulations would be superior compared to placebo, but no statistically significant differences were found when using the pre- specified strict FDA and EMA recommended endpoints. In this regard, the first clinical trial with peppermint oil in a Rome IV-defined IBS population of both primary and secondary care patients showed a negative primary outcome when using these robust stringent endpoints. However, the difference in primary abdominal pain response rate (FDA recommended endpoint) between placebo and small-intestinal release peppermint oil in our study, i.e. 12.4%, is comparable to differences in response rate of other IBS therapeutic trials; e.g. using linaclotide 16 , or plecanatide. 17 It should be noted that in these studies much larger patient populations were studied compared to our study. Although the PERSUADE study is the largest peppermint oil RCT in patients with IBS up to date, we cannot exclude that our study was underpowered to detect statistically significant effects when using these pre-specified stringent endpoints. A type- II error may have occurred since we powered the study for an expected 30% difference that had previously been reported by a meta-analysis. 18 The importance of appropriate outcome measures In general, clinical trials investigating treatment for IBS are hindered by high placebo response rates estimated at around 40% 19 , the chronic relapse-remitting nature, and potentially elusive outcome measures. With regard to the latter, there has been ongoing debate about whether current instruments are able to fully evaluate the complex and heterogeneous IBS condition and represent all relevant dimensions of health for patients with IBS. 20 Both the FDA and EMA recommended endpoints for IBS trials treating more than one IBS-subtype, are dichotomous endpoints of being an abdominal pain- or global relief responder or non-responder, respectively. It has been argued that these dichotomous endpoints provide an incomplete clinical understanding and fail to represent smaller benefits that are clinically important. 21 Therefore, trial results in IBS may reflect a lack of efficacy of treatments given, but could also reflect a lack of appropriate outcome measures. In case of the PERSUADE study, conflicting findings were found across different outcome measures. On the one hand, no statistically significant differences were found between groups in primary outcomes recommended by the FDA and EMA, nor in health-related quality of life scores. This may seem at odds with previous meta-analyses that reported higher efficacy rates. 22 On the other hand,