Lembo, Anthony

INTRODUCTION: Bowel preps for colonoscopy can cause transient changes in gut microbiota. Rifaximin is indicated as IBS-D treatment in adults. This post hoc analysis evaluated effect of time since colonoscopy on rifaximin response for IBS-D. METHODS: Two phase 3 studies (TARGET 1/2) comprised adults who had documented history of colonoscopy <2 y prior to enrollment for IBS evaluation; otherwise they had 1 within 30 d of signed consent. Patients (pts) were randomized to rifaximin 550 mg TID or placebo for 2 wks. Responders, grouped by time from colonoscopy to treatment start (≤60 d or >60 d), were analyzed using LOCF. Composite responders (FDA endpoint) were pts meeting weekly response criteria for abdominal pain (≥30% decrease from baseline in mean weekly pain score [range, 0-6]) and stool consistency (≥50% decrease from baseline in d/wk with Bristol Stool Scale type 6/7 stool) during ≥2 of first 4 wks posttreatment; responders for individual components also were determined. RESULTS: Differences in responder rates between rifaximin and placebo were observed in colonoscopy-timing subgroups (≤60 d or >60 d), with largest differences seen in >60 d group (Figure 1). Among pts who had colonoscopy >60 d prior to starting treatment in TARGET 1, a greater percentage treated with rifaximin (n=109) vs placebo (n=106) were composite (47.7% vs 34.0%; P = 0.04), abdominal pain (53.2% vs 40.6%; P = 0.06), or stool consistency (81.7% vs 63.2%; P = 0.002) responders. For colonoscopy ≤60 d prior to starting treatment, a greater percentage of pts treated with rifaximin (n = 199) vs placebo (n = 208) were composite (45.7% vs 40.9%; P = 0.32), abdominal pain (50.3% vs 42.8%; P = 0.13), or stool consistency (77.4% vs 69.7%; P = 0.08) responders. In TARGET 2, a greater percentage of pts treated with rifaximin (n = 106) vs placebo (n = 97) in colonoscopy >60 d prior group were composite (45.3% vs 32.0%; P = 0.05), abdominal pain (53.8% vs 39.2%; P = 0.04), or stool consistency (71.7% vs 61.9%; P = 0.14) responders. A greater percentage of pts treated with rifaximin (n = 209) vs placebo (n = 223) in colonoscopy ≤60 d prior group were responders, although differences were smaller: composite (47.4% vs 38.1%; P = 0.05), abdominal pain (51.7% vs 44.8%; P = 0.16), and stool consistency (75.1% vs 65.5%; P = 0.03). CONCLUSION: Larger differences in responder rates with rifaximin vs placebo were observed in pts in whom colonoscopy was >60 d from start of IBS-D therapy. This may be related in part to reestablishment of IBS-related gut microbiota dysbiosis; further research is needed.

Abstract Background This manuscript summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance, terminology used, and interpretation of anorectal function testing including anorectal manometry (focused on high‐resolution manometry), the rectal sensory test, and the balloon expulsion test. Based on these measurements, a classification system for disorders of anorectal function is proposed. Methods Twenty‐nine working group members (clinicians/academics in the field of gastroenterology, coloproctology, and gastrointestinal physiology) were invited to six face‐to‐face and three remote meetings to derive consensus between 2014 and 2018. Key recommendations The IAPWG protocol for the performance of anorectal function testing recommends a standardized sequence of maneuvers to test rectoanal reflexes, anal tone and contractility, rectoanal coordination, and rectal sensation. Major findings not seen in healthy controls defined by the classification are as follows: rectoanal areflexia, anal hypotension and hypocontractility, rectal hyposensitivity, and hypersensitivity. Minor and inconclusive findings that can be present in health and require additional information prior to diagnosis include anal hypertension and dyssynergia. Conclusions and Inferences This framework introduces the IAPWG protocol and the London classification for disorders of anorectal function based on objective physiological measurement. The use of a common language to describe results of diagnostic tests, standard operating procedures, and a consensus classification system is designed to bring much‐needed standardization to these techniques.

Background: Irritable bowel syndrome with diarrhea (IBS-D) is a prevalent gastrointestinal (GI) disorder with a varied presentation, often overlapping with other GI and non-GI disorders. Eluxadoline is a locally active mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved for the treatment of IBS-D in adults. As IBS-D is a heterogeneous disease, factors such as patient demographics, symptom severity, and symptom pattern history can potentially inform treatment selection. Methods: Here, we report additional prospectively planned analyses of two large double-blind, placebo-controlled studies (IBS-3001 and IBS-3002) enrolling patients meeting Rome III criteria for IBS-D. Patients were randomized 1:1:1 to receive placebo or eluxadoline 75 mg or 100 mg twice daily. Efficacy (abdominal pain, stool consistency, and composite, simultaneous improvement in both) and safety were assessed for prospectively defined patient subgroups stratified by age, sex, race, presence of comorbidities, and baseline disease characteristics. Results: Across all age, sex, race, comorbidity, and disease characteristic subgroups, a greater proportion of patients were composite responders with both eluxadoline doses as compared with placebo, including patients with a history of depression or a history of gastroesophageal reflux disease. Among patients aged ⩾65 years, a greater proportion of patients receiving eluxadoline 75 mg were composite, abdominal pain, and stool consistency responders compared with those receiving 100 mg. The proportion of patients with at least one adverse event was slightly higher in patients aged ⩾65 years and also in female patients. Conclusions: This analysis suggests that eluxadoline is effective in treating IBS-D across a range of commonly encountered patient types. In contrast to the overall population, patients aged ⩾65 years demonstrated a greater proportion of responders at the lower approved 75 mg eluxadoline dose.

BackgroundOptimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS‐C) are uncertain.ObjectiveThe objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS‐C symptoms.MethodsUsing pooled 12‐week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed.ResultsCorrelations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48–0.54, 0.32–0.39, and 0.61–0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS‐C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%–76% and 71%–82% of weeks with agreement, respectively).ConclusionsAR bridges IBS‐C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.