Lacy, Brian E

Background: In patients with irritable bowel syndrome with constipation (IBS-C), rapid, sustained relief from constipation and abdominal symptoms, such as pain, discomfort, and bloating, can improve quality of life. Objective: This post hoc analysis evaluates the time to constipation and abdominal symptom relief achieved with tenapanor. Design: Post hoc analysis of data pooled from three randomized placebo-controlled studies (phase IIb, T3MPO-1, and T3MPO-2) of tenapanor 50 mg twice daily in patients with IBS-C. Methods: The time to first response for complete spontaneous bowel movement (CSBM) frequency, abdominal pain, discomfort, bloating, and 3-item abdominal score (AS3) were assessed. The AS3 was derived as the average of the weekly scores for abdominal pain, discomfort, and bloating. Cumulative incidences of response over time were estimated using the Kaplan–Meier method. A Cox proportional hazards model was used to assess the effect of baseline and demographic characteristics on the time to first response. Results: Among 1372 patients with IBS-C (684 tenapanor; 688 placebo), median time to first CSBM response was 2 weeks, and median time to abdominal pain, discomfort, bloating, or AS3 response was 4–5 weeks in those treated with tenapanor, with 67.8%–76.7% achieving first response in CSBM frequency and abdominal symptoms by week 12. These time frames were shorter than those observed with the placebo (4 weeks for CSBM and 6–8 weeks for pain, discomfort, bloating, and AS3), of whom 59.1%–69.4% achieved the first response in CSBM and abdominal symptoms by week 12. Higher weekly response rates were observed with tenapanor than with placebo for all endpoints in each week of the 12-week treatment period. Conclusion: This novel post hoc analysis demonstrates that, compared with placebo, tenapanor reduces the time to first response in CSBM frequency and abdominal symptoms and consistently increases the weekly response rate during 12 weeks of treatment. Trial registration: NCT01923428; NCT02621892; NCT02686138.

ABSTRACTIntroductionInvestigation of an evacuation disorder is often pursued in patients with symptoms of obstructive defecation. High‐resolution anorectal manometry (HR‐ARM) is a simple, safe, and widely available test to diagnose pelvic floor dysfunction. A more costly and less accessible test is magnetic resonance defecography (MRD). This study aims to quantify the added value of MRD in diagnosing pelvic floor disorders.MethodsHR‐ARM and MRD performed in patients with a diagnosis of constipation between January 1, 2020 and May 15, 2022 at Mayo Clinic were identified using Epic Slicer Dicer. Univariate and multivariate analyses were used to compare findings on MRD in patients with and without abnormal HR‐ARM. Categorical variables were compared using the Pearson's chi‐square test, and continuous variables were compared using the two‐sample t‐test.ResultsSeventy‐six consecutive patients (81.8% female, 94.8% White, ages 19–82) who underwent both HR‐ARM and MRD were included. The majority had evidence of dyssynergia on HR‐ARM (n = 49, 64.5%). Patients with dyssynergia on HR‐ARM were significantly more likely to have prolonged balloon expulsion at both > 60 and > 30 s (p < 0.001) and incomplete gel expulsion on MRD (p < 0.001). However, they were not more likely to have a clinically significant rectocele measuring > 2 cm (p = 0.17) or evidence of rectal prolapse (p = 0.07).DiscussionAnatomic findings on MRD were similar between patients with and without evidence of dyssynergia identified by HR‐ARM. In this retrospective review, simultaneously undergoing MRD in addition to HR‐ARM does not appear to provide significant additional diagnostic information to guide therapeutic recommendations. Large prospective studies to evaluate the added value of MRD are needed.

Summary Background MRx1234 is a live biotherapeutic product that contains a strain of Blautia hydrogenotrophica. It is in development for the treatment of irritable bowel syndrome (IBS). Aims To assess the efficacy and safety of MRx1234 in patients with IBS with predominant constipation (IBS‐C) or diarrhoea (IBS‐D) Methods We conducted a multicentre, randomised, double‐blind, placebo‐controlled, phase 2 trial. Patients aged 18–70 years in two parallel cohorts (IBS‐C; IBS‐D) were randomised (1:1) to MRx1234 or placebo for 8 weeks. The primary efficacy endpoint was overall responder rate—a composite of improved bowel habit (IBS‐C: stool frequency; IBS‐D: stool consistency) and abdominal pain intensity—for ≥50% of the treatment period in each cohort. Statistical testing was at a one‐sided 0.10 significance level. Results Of 366 randomised patients (164 IBS‐C; 202 IBS‐D), 365 received any study medication (177 MRx1234, 188 placebo). Numerically, although not statistically significantly different, more patients who received MRx1234 than placebo were overall responders in the IBS‐C (25.0% vs. 17.1%) and IBS‐D (23.4% vs. 17.8%) cohorts. Similar results were observed in the additional combined cohort analysis (24.1% vs. 17.5%; p = 0.063). For the components of the primary endpoint, significantly more patients on MRx1234 than placebo reported improvement in bowel habit in the IBS‐C, IBS‐D and combined cohorts, while improvements in abdominal pain were observed in each cohort. The safety profile of MRx1234 was similar to placebo. Conclusions MRx1234 has the potential to become a novel, safe treatment option for patients with IBS‐C or IBS‐D, and for those who have mixed symptoms or transition between subtypes. ClinicalTrials.gov #NCT03721107.

SummaryBackgroundGastroparesis has a significant negative impact on patients’ quality of life. Only one medication is approved for gastroparesis and it is associated with a significant risk of side effects.AimTo assess the willingness of patients to take risks associated with medications to treat gastroparesis symptoms.MethodsWe developed a questionnaire to assess medication risk‐taking behaviour in patients identified as having documented gastroparesis (consistent symptoms, normal upper endoscopy, delayed gastric emptying). The survey assessed demographics, symptoms, medication use, anxiety, depression and impulsivity. A standard reference gamble evaluated respondents’ willingness to take medication risks.ResultsTwo hundred seven questionnaires were mailed to patients, 103 questionnaires were completed. Seventy‐six percent were female; the mean age was 48 years; average duration of gastroparesis symptoms was 10 years. Self‐reported symptom severity was severe in 52% and moderate in 32%. Gastroparesis patients reported that they would accept a median 13.4% risk of sudden death to cure their symptoms using a hypothetical medication. Self‐reported gastroparesis symptom severity and Gastroparesis Cardinal Symptom Index scores correlated significantly with increased willingness to take risks associated with medications to treat gastroparesis, while anxiety was negatively associated.ConclusionsGastroparesis patients are willing to accept markedly high risks with a hypothetical medication to cure their symptoms. Patients with severe gastroparesis symptoms and higher Gastroparesis Cardinal Symptom Index scores were more willing to take these risks. This study, the first to quantify gastroparesis patients’ willingness to accept medication associated risks, should help clinicians through the complex maze of gastroparesis therapies and their associated risks and benefits.