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Efficacy and safety of peppermint oil in IBS 165 7 Detailed inclusion and exclusion criteria Patients had to be between 18 and 75 years of age and needed to fulfill the Rome IV diagnostic criteria for IBS. If alarm symptoms were present ( e.g. unexplained rectal blood loss or weight loss), a colonoscopy or other relevant tests were performed to exclude organic disease. Exclusion criteria were inability to read or understand Dutch, history of GI disorders such as inflammatory bowel disease, celiac disease, or thyroid dysfunction (if not well-regulated), history of major abdominal surgery or radiotherapy interfering with GI function. An uncomplicated appendectomy, cholecystectomy, or hysterectomy were allowed unless within six months prior to screening. Other exclusion criteria were use of peppermint oil capsules in the three months prior to screening, a known allergic reaction to peppermint oil, current drug abuse, and a history of liver or gallbladder/biliary disease. Women had to use contraceptives and have a negative urine pregnancy test, or be postmenopausal for at least two years. The use of one antidepressant or one PPI was allowed, if a patient had been and would stay on a stable dose. Prohibited concomitant medications included opioids, prokinetics, stimulant laxatives ( i.e. bisacodyl), linaclotide, prucalopride, and anti-spasmodic drugs. Regular use of NSAIDs, antibiotics, osmotic laxatives, and antidiarrheal drugs was prohibited. Treatment allocation Randomization was done with ALEA software using the minimization method, accounted for inclusion center, IBS subtypes, gender, and age. A random element was incorporated into each step of the minimization to ensure allocation concealment. As such, when an imbalance of more than two subjects per treatment group existed (in a specific inclusion center), there was a 10% chance that the subsequent randomization would overrule this already existing imbalance. Statistical analysis of secondary outcomes For secondary continuous outcomes, treatment effects were analyzed at different time- points after correction for baseline using linear mixed models with treatment group, minimization variables, time, and time*group interaction as fixed-effects. A likelihood- based approach was used to deal with missing values. Different covariance structures (unstructured, autoregressive moving average 1.1, heterogeneous Toeplitz, heterogeneous first-order-autoregressive) were explored to choose the best based on