SMARCA4-Deficient Undifferentiated Esophageal Carcinoma: A Clinical Case Series and Literature Review.

PURPOSE: Undifferentiated carcinoma of the esophagus (UEC) is a rare malignancy. Deficiency in SMARCA genes, critical for chromatin regulation, has been observed in cases of UEC. Research in UEC is sparse, however, and we present a case series along with a comprehensive review of the literature. CASE SERIES: Case 1 is a 49-year-old female with abdominal pain and dysphagia and esophagogastroduodenoscopy (EGD) showing a friable mass at the gastroesophageal (GE) junction. Biopsies showed a poorly differentiated neoplasm and immunohistochemistry showed loss for SMARCA4. With metastatic disease, she agreed to undergo palliative chemotherapy and radiation, passing away at 4 months. Case 2 is an 88-year-old male with dysphagia, nausea, vomiting, and distal esophageal mass with biopsy showing a malignancy with loss of SMARCA4 expression. Due to extensive metastases, he was counseled on hospice care. Case 3 is a 53-year-old male with extensive alcohol and smoking history presenting with hematemesis, passing away shortly. Posthumous histopathology consistent with undifferentiated SMARCA4-deficient carcinoma of the esophagus. Results of the literature review indicate a predilection towards males (75.0%) and a variable age range (39-88 years). Majority (76.2%) reported with a distal esophagus location. Metastatic disease was common at initial presentation. Median survival was 2.60 months. Some were managed with chemotherapy and radiation. CONCLUSIONS: Research in SMARCA-deficient UEC is very limited. It is more common in men, age is variable, and associated with Barret's esophagus. Further research is necessary to better understand it and to establish treatment guidelines; however, it is clear that SMARCA4-deficient UEC carries a significantly poor prognosis.

Prevalence and determinants of postprandial diarrhea in a tertiary care center.

BACKGROUND AND AIMS: Postprandial diarrhea (PPD) is commonly seen in patients with disorders of gut-brain interaction (DGBI), but the factors associated with it have not been well studied. In this study, we aim to study the burden, impact, and predictors of PPD using a clinical cohort of DGBI patients. METHODS: This study included patients with chronic diarrhea fulfilling ROME IV criteria for irritable bowel syndrome (IBS) or functional diarrhea (FDiarr). PPD was defined as patients reporting mushy/watery stools following meals ≥30% of the time in the last 3 months using a ROME IV question on PPD. Age, sex, and BMI, the severity of diarrhea, abdominal pain, depression, anxiety, somatization, and quality of life were assessed using validated measures. Person's chi-square test and Student's t-test were used to compare variables. A multiple linear regression model with backward elimination was done to determine predictors of PPD severity. KEY RESULTS: Of 213 eligible patients, more than three-fourth of patients (75.6%) had PPD. Women (79.0%, p = 0.037), patients with ROME IV diagnosis of IBS-D (90.5%, p = 0.002), and functional dyspepsia (83.2%, p = 0.014), and those with a history of cholecystectomy (CCY) (95.5%, p = 0.022) were more likely to report PPD. PPD patients experienced more severe abdominal pain, diarrhea, and decreased quality of life (QoL) but showed no significant difference in BMI, anxiety, depression, sleep, or somatization. In our regression model, female sex and history of CCY were independent predictors of PPD. CONCLUSIONS AND INFERENCES: PPD is frequently reported among chronic diarrhea patients and is associated with more severe GI symptoms and decreased QoL. Female sex and CCY predict PPD, while psychological factors do not.

Clinical Outcomes and Safety of Upper Endoscopy While on Glucagon-Like Peptide-1 Receptor Agonists.

Glucose-like peptide-1-receptor agonists (GLP-1RAs) have become integral to the management of type 2 diabetes and obesity. GLP-1RAs work in part through delaying gastric emptying, raising concerns about retained gastric contents (RGC) during esophagogastroduodenoscopy (EGD).1 The American Society of Anesthesiologists currently recommends holding GLP-1RAs for 1 dosing cycle before elective procedures, however, the American Gastroenterological Association (AGA) advocates proceeding with endoscopy in asymptomatic patients adhering to standard perioperative protocols without medication withholding and suggests implementing a liquid diet the day before endoscopy in lieu of stopping the medication.2,3 This variability in recommendations stems largely from a lack of GLP-1RA outcomes data from which to draw evidence-based conclusions.

Colonoscopy Utilization in Elderly Patients with Dementia: Characteristics, Complications, and Charges in a National Matched-Cohort Analysis.

BACKGROUND: It is projected that the elderly population will continue to increase. Many will develop chronic conditions such as dementia. AIMS: Our aims are to describe the utilization of colonoscopy among patients with dementia and compare outcomes in those with and without dementia. METHODS: This population-based analysis utilized the National Inpatient Sample (NIS) during 2019. Patients with dementia over the age of 60 years receiving colonoscopy were identified utilizing ICD-10 codes. Logistic regression was used for propensity score matching between the comparison groups. A Greedy one-to-one matching algorithm was utilized along with standardized mean differences to assess balance. Mcnemar test, signed rank sum, and paired t-test were used to compare the outcomes. RESULTS: Initially, 50,692 patients without dementia were compared with 4323 patients with dementia. Patients with dementia were more likely to be female, older, less likely White, had lower income, and more likely to be on Medicare. In the matched comparison (4176 in each group), complication analysis showed that patients with dementia did not have higher colonoscopy-related complications. They did have higher rates of other complications including renal/AKI (p = 0.0042), pulmonary/pneumonia (p = 0.003), cerebrovascular accidents (p = 0.0063), and sepsis (< 0.0001). Patients with dementia were also less likely to have routine discharges (< 0.0001), had longer hospital stays (< 0.0001), and higher hospital costs (< 0.0001). CONCLUSIONS: Elderly patients with dementia have similar colonoscopy-related complications as patients without dementia. However, they do have higher complications in general. The decision whether to perform colonoscopy in this patient population is multifactorial. A careful assessment of a dementia patient's history can help with this decision.

Endometriosis Is Associated with Higher Healthcare Utilization and Upper Gastrointestinal Symptoms.

Endometriosis is a chronic inflammatory disease affecting 10%-15% of women, with symptoms including abdominopelvic pain, dysmenorrhea, and menorrhagia. Up to 90% experience gastrointestinal (GI) symptoms including constipation, bloating, and nausea/vomiting.1 Females with endometriosis are at 3-5 times greater risk of developing IBS than healthy women,2,3 with rates of IBS as high as 52%.4 Another study demonstrated 37% of those with IBS also had endometriosis, much higher than the typical prevalence of endometriosis.5 Patients with IBS and endometriosis experience lower pain thresholds and more painful menstrual cycles than those with either condition alone. This amplification of pain experiences can increase health care utilization and decrease quality of life.

Clinical outcomes before and after prucalopride treatment: an observational study in patients with chronic idiopathic constipation in the USA.

INTRODUCTION: This real-world US-based claims study compared constipation-related symptoms and complications 6 months before and after prucalopride initiation in adults with chronic idiopathic constipation (CIC). METHODS: This observational, retrospective cohort analysis used the IBM MarketScan® Commercial Claims and Encounters and the Medicare Supplemental databases (January 2015-June 2020). Prucalopride-treated patients (≥18 years old) who had ≥1 constipation-related International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnosis code during the baseline or study period were included. The proportions of patients with constipation-related symptoms (abdominal pain, abdominal distension [gaseous], incomplete defecation, and nausea) and constipation-related complications (anal fissure and fistula, intestinal obstruction, rectal prolapse, hemorrhoids, perianal venous thrombosis, peri-anal/peri-rectal abscess, and rectal bleeding) were examined. Constipation-related symptoms and complications were identified using ICD-10-CM, ICD-10-Procedure Coding System, or Current Procedural Terminology codes. Data were stratified by age (overall, 18-64 years, ≥65 years). RESULTS: This study included 690 patients: mean (standard deviation) patient age was 48.0 (14.7) years and 87.5% were women. The proportions of patients overall with constipation-related symptoms decreased 6 months after prucalopride initiation (abdominal pain [50.4% vs 33.3%, P<0.001]; abdominal distension [gaseous] [23.9% vs 13.3%, P<0.001]; and nausea [22.6% vs 17.7%, P<0.01]; no improvements observed for incomplete defecation). Similarly, the proportions of patients overall with constipation-related complications decreased 6 months after prucalopride initiation (intestinal obstruction [4.9% vs 2.0%, P<0.001]; hemorrhoids [10.7% vs 7.0%, P<0.05]; and rectal bleeding [4.1% vs 1.7%, P<0.05]). DISCUSSION: This study suggests that prucalopride may be associated with improved constipation-related symptoms and complications 6 months after treatment initiation.

Burden and Treatment of Chronic Upper GI Symptoms and Diagnoses: A Nationwide Study.

BACKGROUND & AIMS: Chronic gastrointestinal (GI) symptoms are a common reason for seeking medical care. We aim to determine the rates of ambulatory care use and to characterize demographics, work-up, and treatment (pharmacologic and nonpharmacologic) for patients with chronic upper GI symptoms and conditions in the United States. METHODS: Estimates of annual visits for the most common upper GI symptoms and diagnoses including gastroesophageal reflux disease, dyspepsia, nausea and vomiting, and gastroparesis were recorded from the 2007-2015 National Ambulatory Medical Care Surveys. Only chronic conditions, defined as >3 months, were included. We calculated the weighted proportion of ambulatory visits associated with pharmacologic, nonpharmacologic treatment (eg, diet, complementary and alternative medicine), or both. RESULTS: A total of 116,184,475 weighted ambulatory visits were identified between the years of 2007 and 2015 for adults (average of 12,909,386 annual visits) with chronic upper GI symptoms and diagnoses. Gastroesophageal reflux disease was the most common reason for an ambulatory visit (n = 11,200,193), followed by dyspepsia (n = 1,232,598), nausea and vomiting (n = 714,834), and gastroparesis (n = 140,312). Pharmacologic treatment was more common than nonpharmacologic treatment (44.7% vs 28.5%). A total of 37.6% of patients were not receiving treatment at the time of the visit. These treatment patterns did not significantly change over the time of our study. Upper endoscopies were the most ordered test, representing 7.5% of all investigated upper GI symptoms. CONCLUSIONS: Chronic upper GI symptoms and diagnoses account for a high number of annual health care visits, both in primary care and specialty care. Although there are several treatments, many of these patients are not on any treatments.

Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis.

INTRODUCTION: This post hoc analysis evaluated the efficacy of tenapanor on abdominal symptoms in patients with irritable bowel syndrome with constipation. Abdominal symptoms assessed included pain, discomfort, bloating, cramping, and fullness. METHODS: The abdominal symptom data were pooled from 3 randomized controlled trials (NCT01923428, T3MPO-1 [NCT02621892], and T3MPO-2 [NCT02686138]). Weekly scores were calculated for each abdominal symptom, and the Abdominal Score (AS) was derived as the average of weekly scores for abdominal pain, discomfort, and bloating. The overall change from baseline during the 12 weeks was assessed for each symptom weekly score and the AS. The AS 6/12-week and 9/12-week response rates (AS improvement of ≥2 points for ≥6/12- or ≥9/12-week) were also evaluated. The association of weekly AS response status (reduction of ≥30%) with weekly complete spontaneous bowel movement (CSBM) status (=0 and >0) was assessed. RESULTS: Among 1,372 patients (684 tenapanor [50 mg twice a day] and 688 placebo), the least squares mean change from baseline in AS was -2.66 for tenapanor vs -2.09 for placebo ( P < 0.0001). The 6/12-week AS response rate was 44.4% for tenapanor vs 32.4% for placebo ( P < 0.0001), and for 9/12-week AS, 30.6% for tenapanor vs 20.5% for placebo ( P < 0.0001). A significant association between weekly CSBM status and weekly AS response status was observed each week ( P < 0.0001), with a greater proportion achieving an AS reduction in patients with >0 CSBMs in a week. DISCUSSION: Tenapanor significantly reduced abdominal symptoms in patients with irritable bowel syndrome with constipation, particularly pain, discomfort, and bloating measured by AS, compared with placebo.

The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Neurokinin receptor 1 antagonists are effective in reducing nausea and vomiting in chemotherapy-induced emesis. We investigated the safety and efficacy of tradipitant, a neurokinin receptor 1 antagonist, in patients with idiopathic and diabetic gastroparesis. METHODS: A total of 201 adults with gastroparesis were randomly assigned to oral tradipitant 85 mg (n = 102) or placebo (n = 99) twice daily for 12 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. Blood levels were monitored for an exposure-response analysis. The primary outcome was change from baseline to week 12 in average nausea severity, measured by daily symptom diary. RESULTS: The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12 (difference in nausea severity change drug vs placebo; P = .741) or prespecified secondary endpoints. Post hoc analyses were performed to control for drug exposure, rescue medications, and baseline severity inflation. Subjects with high blood levels of tradipitant significantly improved average nausea severity beginning at early time points (weeks 2-4). In post hoc sensitivity analyses, tradipitant treatment demonstrated strengthened effects, with statistically significant improvements in nausea at week 12. CONCLUSIONS: Although tradipitant did not reach significance in the ITT population, a pharmacokinetic exposure-response analysis demonstrated significant effects with adequate tradipitant exposure. When accounting for confounding factors such as baseline severity inflation and rescue medication, a statistically significant effect was also observed. These findings suggest that tradipitant has potential as a treatment for the symptom of nausea in gastroparesis. (ClincialTrials.gov, Number: NCT04028492).

Long-term safety of tenapanor in patients with irritable bowel syndrome with constipation in the T3MPO-3 study.

BACKGROUND: Tenapanor, a first-in-class, minimally systemic inhibitor of intestinal sodium/hydrogen exchanger isoform 3 (NHE3), is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults based on two randomized, placebo-controlled, phase III studies (T3MPO-1 [NCT02621892], T3MPO-2 [NCT02686138]). The open-label T3MPO-3 extension study (NCT02727751) enrolled patients who completed these studies to investigate long-term safety and tolerability of tenapanor. METHODS: Patients who completed T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) were eligible for enrollment in T3MPO-3. Patients in T3MPO-3 received open-label tenapanor 50 mg twice a day for up to an additional 39 (T3MPO-1) or 26 (T3MPO-2) weeks. Treatment-emergent adverse events (TEAEs) were evaluated in the entire T3MPO-3 safety population and in patients who received a total of ≥52 weeks of tenapanor. KEY RESULTS: A total of 312 patients were enrolled in T3MPO-3; 90 received ≥52 weeks of tenapanor. TEAEs were reported in 117 (37.5%) patients in the safety population and in 52 (57.8%) patients who received ≥52 weeks of tenapanor. Diarrhea was the most common TEAE, occurring in 10.6% of the safety population and in 11.1% of patients who received ≥52 weeks of tenapanor. Most cases were mild or moderate in severity, with only two severe cases reported in the safety population. No deaths occurred during the T3MPO-3 study. CONCLUSIONS: Tenapanor was tolerable over ≥52 weeks of treatment and showed similar safety to that seen in shorter studies. Combined results of the T3MPO studies indicate that tenapanor is a valuable new treatment option for patients with IBS-C.

How Would You Manage This Patient With Recurrent Diverticulitis? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Acute diverticulitis, which refers to inflammation or infection, or both, of a colonic diverticulum, is a common medical condition that may occur repeatedly in some persons. It most often manifests with left-sided abdominal pain, which may be associated with low-grade fever and other gastrointestinal symptoms. Complications may include abscess, fistula formation, perforation, and bowel obstruction. The American College of Physicians recently published practice guidelines on the diagnosis and management of acute diverticulitis, the role of colonoscopy after resolution, and interventions to prevent recurrence of this condition. Among the recommendations were the use of abdominal computed tomography (CT) scanning in cases where there was diagnostic uncertainty, initial management of uncomplicated cases in the outpatient setting without antibiotics, referral for colonoscopy after an initial episode if not performed recently, and discussion of elective surgery to prevent recurrent disease in patients with complicated diverticulitis or frequent episodes of uncomplicated disease. Here, 2 gastroenterologists with expertise in acute diverticulitis debate CT scanning for diagnosis, antibiotics for treatment, colonoscopy to screen for underlying malignancy, and elective surgery to prevent recurrent disease.

Prevalence and Associated Factors of Bloating: Results From the Rome Foundation Global Epidemiology Study.

BACKGROUND & AIMS: Bloating is a common symptom in the general population and among disorders of gut-brain interaction, although its prevalence has not been well characterized. The aim of this study was to report the prevalence of bloating as a symptom in the worldwide population and to identify factors associated with this symptom in the general population. METHODS: Rome Foundation Global Epidemiology Study internet survey data were analyzed. After excluding respondents with potential organic causes of bowel symptoms, the current analysis included 51,425 individuals in 26 countries. Data included diet, medical history, quality of life, and Rome IV diagnostic questions. Presence of bloating was defined as experiencing bloating at least once per week for the last 3 months. Descriptive statistics estimated prevalence by country, region, and disorder of gut-brain interaction diagnosis. Logistic regression evaluated predictors of bloating. RESULTS: Nearly 18% of the global study population reported bloating (ranging from 11% in East Asia to 20% in Latin America). Prevalence decreased with age and women were approximately twice as likely as men to report bloating. More than one-half of respondents who reported weekly epigastric pain (71.39%), nausea (59.7%), or abdominal pain (61.69%) also reported bloating at least once per week. In logistic regression, the strongest associations were with abdominal pain (odds ratio, 2.90) and epigastric pain (odds ratio, 2.07). CONCLUSIONS: Bloating is common throughout the world. Nearly 18% of the general population experience bloating at least once per week. Reported bloating prevalence is lower in older age groups, most common in women, and strongly associated with abdominal pain.

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations. RESULTS: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone. DISCUSSION: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

What Is Unspecified Functional Bowel Disorder? A Commonly Seen, Rarely Recognized, and Poorly Understood Diagnosis.

INTRODUCTION: Unspecified functional bowel disorder (FBD-U) is a Rome IV diagnosis of exclusion and occurs when patients report bowel symptoms but do not meet the criteria for other functional bowel disorders (FBD; irritable bowel syndrome [IBS], functional constipation [FC], functional diarrhea [FDr], or functional bloating). Previous research suggests that FBD-U is as/more common than IBS. METHODS: One thousand five hundred one patients at a single-center tertiary care center completed an electronic survey. Study questionnaires included Rome IV Diagnostic Questionnaires, anxiety, depression, sleep, health care utilization, and bowel symptom severity measures. RESULTS: Eight hundred thirteen patients met Rome IV criteria for a FBD and 194 patients (13.1%) met criteria for FBD-U, representing the second most common FBD after IBS. Severity of abdominal pain, constipation, and diarrhea were lower in FBD-U compared with other FBD, whereas health care utilization was similar among the groups. Scores on measures of anxiety, depression, and sleep disturbances were similar in FBD-U compared with FC and FDr but were less severe than IBS. Between 25% and 50% of patients with FBD-U did not meet Rome IV criteria for other FBD due to timing of onset of the target symptom (e.g., constipation for FC, diarrhea for FDr, and abdominal pain for IBS). DISCUSSION: FBD-U, by Rome IV criteria, is highly prevalent in clinical settings. These patients are not represented in mechanistic studies or clinical trials for not having met Rome IV criteria for other FBD. Making future Rome criteria less stringent would minimize the number fulfilling criteria for FBD-U and maximize the true representation of FBD in clinical trials.

Efficacy and safety of olorinab, a full agonist of the cannabinoid receptor 2, for the treatment of abdominal pain in patients with irritable bowel syndrome: Results from a phase 2b randomized placebo-controlled trial (CAPTIVATE).

BACKGROUND: Olorinab is a highly selective, peripherally acting, full agonist of cannabinoid receptor 2. This study assessed the efficacy and safety of olorinab to treat abdominal pain in patients with irritable bowel syndrome with diarrhea (IBS-D) and constipation (IBS-C). METHODS: CAPTIVATE was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial. Eligible participants aged 18-70 years with IBS-C and IBS-D diagnosed per Rome IV received olorinab 10 mg, 25 mg, or 50 mg three times daily (TID) or placebo TID for 12 weeks. The primary endpoint was the change in patient-reported average abdominal pain score (AAPS) from baseline to Week 12. KEY RESULTS: A total of 273 participants were randomized to receive olorinab 10 mg (n = 67), olorinab 25 mg (n = 67), olorinab 50 mg (n = 69), or placebo (n = 70). Although a treatment response was observed across all groups, the weekly change in average AAPS from baseline to Week 12 was not significantly different between placebo and any olorinab dose. In a prespecified subgroup analysis of participants with a baseline AAPS ≥6.5, olorinab 50 mg (n = 35) significantly improved AAPS compared with placebo (n = 30) (p = 0.014). Adverse event rates were comparable between olorinab and placebo and there were no reported serious adverse events or deaths. CONCLUSION AND INFERENCES: Although olorinab was well-tolerated and improved weekly AAPS, the primary endpoint was not met. However, in participants with moderate-to-severe pain at baseline (AAPS ≥6.5), olorinab 50 mg significantly improved weekly AAPS compared with placebo. CLINICALTRIALS: gov: NCT04043455.

Randomized Placebo-Controlled Phase 3 Trial of Vibrating Capsule for Chronic Constipation.

BACKGROUND & AIMS: Despite therapeutic advances, effective treatments for chronic constipation remain an unmet need. The vibrating capsule is a nonpharmacologic, orally ingested, programmable capsule that vibrates intraluminally to induce bowel movements. We aimed to determine the efficacy and safety of the vibrating capsule in patients with chronic constipation. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial of patients with chronic constipation, who were randomized to receive either a vibrating or placebo capsule, once daily, 5 days a week for 8 weeks. The primary efficacy end points were an increase of 1 or more complete spontaneous bowel movements per week (CSBM1 responder) or 2 or more CSBMs per week (CSBM2) from baseline during at least 6 of the 8 weeks. Safety analyses were performed. RESULTS: Among 904 patients screened, 312 were enrolled. A greater percentage of patients receiving the vibrating capsule achieved both primary efficacy end points compared with placebo (39.3% vs 22.1%, P = .001 for CSBM1; 22.7% vs 11.4% P = .008 for CSBM2). Significantly greater improvements were seen with the vibrating capsule for the secondary end points of straining, stool consistency, and quality-of-life measures compared with placebo. Adverse events were mild, gastrointestinal in nature, and similar between groups, except that a mild vibrating sensation was reported by 11% of patients in the vibrating capsule group, but none withdrew from the trial. CONCLUSIONS: In patients with chronic constipation, the vibrating capsule was superior to placebo in improving bowel symptoms and quality of life. The vibrating capsule was safe and well tolerated. (Clinical trials.gov, Number: NCT03879239).