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).

Comparative profiles of lubiprostone, linaclotide, and elobixibat for chronic constipation: a systematic literature review with meta-analysis and number needed to treat/harm.

OBJECTIVE: To comprehensively evaluate the efficacy, safety, patient symptoms, and quality-of-life (QoL) of lubiprostone, linaclotide, and elobixibat as treatment for chronic constipation (CC). DESIGN: Systematic literature review (SLR) and meta-analysis (MA). Literature searches were conducted on PubMed and Embase using the Ovid platform. METHODS: SLR including randomized controlled trials (RCTs) and observational studies was conducted to identify the overall efficacy and safety of lubiprostone, linaclotide, and elobixibat. Thereafter, MA was performed using only RCTs. The number needed to treat (NNT) and number needed to harm (NNH) analyses were additionally conducted. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was efficacy regarding change in spontaneous bowel movements. Secondary outcomes included safety, constipation-related symptoms, and QoL. RESULTS: Twenty-four studies met the inclusion criteria for the SLR: 17 RCTs, 4 observational studies, and 3 single-arm trials. Feasibility assessment for the MA resulted in 14 studies available for safety data analysis, and 8 available for efficacy analysis, respectively. Three drugs showed similar efficacy in the MA and NNT analysis. However, the NNH analysis revealed distinct safety profiles: lubiprostone, linaclotide, and elobixibat were linked to the highest risk of nausea, diarrhea, and abdominal pain, respectively. CONCLUSION: The current study provides an updated overview of the efficacy, safety, patient symptoms, and QoL of the three drugs with different mechanisms of action for CC treatment.The findings could help physicians adopt an individualized approach for treating patients with CC in clinical practice.

Capsules for the Diagnosis and Treatment of Gastrointestinal Motility Disorders- A Game Changer.

PURPOSE OF REVIEW: Over the last few decades, there have been remarkable strides in endoscopy and radiological imaging that have advanced gastroenterology. However, the management of neurogastroenterological disorders has lagged behind, in part handicapped by the use of catheter-based manometry that is both non-physiological and uncomfortable. The advent of capsule technology has been a game changer for both diagnostic and therapeutic applications. RECENT FINDINGS: Here, we discuss several capsule devices that are available or under investigation. There are three technologies that are FDA approved. Wireless motility capsule measures pH and pressure and provides clinically impactful information regarding gastric, small intestine and colonic transit, without radiation that has been demonstrated to guide management of gastroparesis, dyspepsia and constipation. Wireless ambulatory pH monitoring capsule is currently the gold standard for assessing gastroesophageal acid reflux. In the therapeutics arena, an orally ingested vibrating capsule has been recently FDA approved for the treatment of chronic constipation, supported by a robust phase 3 clinical trial which showed significant improvement in constipation symptoms and quality of life. There are several capsules currently under investigation. Smart capsule bacterial detection system and Capscan® are capsules that can sample fluid in the small or large bowel and provide microbiome analysis for detection of small intestinal bacterial (SIBO) or fungal overgrowth (SIFO). Another investigational gas sensing capsule analyzing hydrogen, CO2, volatile fatty acids and capsule orientation, can measure regional gut transit time and luminal gas concentrations and assess gastroparesis, constipation or SIBO. Therapeutically, other vibrating capsules are in development. Innovations in capsule technology are poised to transform our ability to investigate gut function physiologically, and non-invasively deliver targeted treatment(s), thereby providing both accurate diagnostic information and luminally-directed, safe therapy.

Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

BACKGROUND: Bloating is a bothersome symptom in irritable bowel syndrome with constipation (IBS-C). AIM: To evaluate plecanatide efficacy in patients with IBS-C stratified by bloating intensity. METHODS: Pooled phase 3 data (2 randomized, controlled IBS-C trials) from adults treated with plecanatide 3 mg or placebo for 12 weeks were analyzed. Patients were stratified post-hoc by baseline bloating severity (11-point scale: mild [≤ 5] and moderate-to-severe [> 5]). Assessments included change from baseline in bloating, abdominal pain, and complete spontaneous bowel movement (CSBM) frequency. Abdominal pain and bloating composite responders were defined as patients with ≥ 30% improvement from baseline in both bloating and abdominal pain at Week 12. RESULTS: At baseline, 1104/1436 patients with IBS-C (76.9%) reported moderate-to-severe bloating. In the moderate-to-severe bloating subgroup, plecanatide significantly reduced bloating severity versus placebo (least-squares mean change [LSMC]: - 1.7 vs - 1.3; P = 0.002), reduced abdominal pain (- 1.7 vs - 1.3; P = 0.006), and increased CSBM frequency (1.4 vs 0.8; P < 0.0001). In the mild bloating subgroup, significant improvements were observed with plecanatide versus placebo for abdominal pain (LSMC: - 1.3 vs - 1.0; P = 0.046) and CSBM frequency (2.0 vs 1.2; P = 0.003) but not bloating (- 0.9 vs - 0.8; P = 0.28). A significantly greater percentage of patients were abdominal pain and bloating composite responders with plecanatide versus placebo (moderate-to-severe bloating: 33.6% vs 26.8% [P = 0.02]; mild bloating: 38.4% vs 27.2% [P = 0.03]). CONCLUSION: Plecanatide treatment improved IBS-C abdominal and bowel symptoms, including in those who present with moderate-to-severe bloating.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.

Pathoetiology of Levator Ani Syndrome and Its Treatment With Translumbosacral Neuromodulation Therapy.

INTRODUCTION: The pathoetiology and treatment of levator ani syndrome (LAS) remain unclear. METHODS: We evaluated pathophysiology using translumbosacral motor-evoked potentials and anorectal manometry in patients with LAS and compared with healthy controls. A cohort underwent translumbosacral neuromodulation therapy (TNT). RESULTS: Lumbar and sacral motor-evoked potential latencies were prolonged in 32 patients with LAS compared with 31 controls ( P < 0.013), with higher prevalence of anal neuropathy ( P = 0.026). TNT improved anorectal pain ( P = 0.003) and neuropathy ( P < 0.02) in 13 patients with LAS. DISCUSSION: Patients with LAS demonstrate significant lumbosacral neuropathy that may cause anorectal pain. TNT improved anorectal pain and neuropathy, providing a novel therapeutic option.

Recognizing and Defining Occasional Constipation: Expert Consensus Recommendations.

Constipation is a common problem, affects 15% of the population, and is often self-diagnosed and self-managed. Over the past 3 decades, there have been significant advances in our understanding and management of chronic constipation, with the emerging recognition that occasional constipation (OC) is another subtype that falls outside current classifications. The purpose of this review was to describe the process of developing and proposing a new definition for OC based on expert consensus and taking into consideration the multifactorial nature of the problem such as alterations in bowel habit that include stool frequency and difficulty with stool passage, perception of the sufferer, duration of symptoms, and potential responsiveness to treatment. Leading gastroenterologists from 5 countries met virtually on multiple occasions through an online digital platform to discuss the problem of OC and recommended a practical, user-friendly definition: "OC can be defined as intermittent or occasional symptomatic alteration(s) in bowel habit. This includes a bothersome reduction in the frequency of bowel movements and/or difficulty with passage of stools but without alarming features. Bowel symptoms may last for a few days or a few weeks, and episodes may require modification of lifestyle, dietary habits and/or use of over-the-counter laxatives or bulking agents to restore a satisfactory bowel habit." Prospective studies are required to validate this definition and determine OC prevalence in the community. This review highlights current knowledge gaps and could provide impetus for future research to facilitate an improved understanding of OC and development of evidence-based management guidelines.

Bacterial overgrowth and lactose intolerance: how to best assess.

PURPOSE OF REVIEW: To provide an up-to-date review on the clinical assessment of two important gastrointestinal problems with overlapping symptomatology but diverse cause and testing methods. Small intestinal bacterial overgrowth (SIBO) is characterized by the presence of excess bacteria in the small intestine associated with bloating, distention, gas, and diarrhea. Lactose intolerance is caused by lactase enzyme deficiency in the small bowel mucosa leading to lactose malabsorption and symptoms of bloating, gas, and diarrhea. RECENT FINDINGS: SIBO is assessed by hydrogen/methane breath test using glucose as a substrate and/or small bowel aspirate and culture but these tests have shortcomings. Consequently, several new diagnostic techniques, including novel capsule technologies and other approaches are being evaluated. Lactose intolerance can be assessed by hydrogen/methane breath test using lactose as a substrate, or small bowel mucosal lactase assay, genetic testing and lactose tolerance test, although the efficacy and practicality of these diagnostic modalities are not equal. SUMMARY: In clinical practice, gas, bloating, distention, pain, and diarrhea are common gastrointestinal symptoms that often remain unexplained when routine gastrointestinal endoscopy, imaging, and stool tests are negative. These patients should be evaluated for SIBO and/or food intolerances including lactose intolerance.

Translumbosacral Anorectal Magnetic Stimulation Test for Fecal Incontinence.

BACKGROUND: Neuropathy may cause fecal incontinence and mixed fecal incontinence/constipation, but its prevalence is unclear, partly due to the lack of comprehensive testing of spino-anorectal innervation. OBJECTIVE: This study aimed to develop and determine the clinical usefulness of a novel test, translumbosacral anorectal magnetic stimulation for fecal incontinence. DESIGN: This observational cohort study was conducted from 2012 to 2018. SETTINGS: This study was performed at a tertiary referral center. PATIENTS: Patients with fecal incontinence, patients with mixed fecal incontinence/constipation, and healthy controls were included. INTERVENTIONS: A translumbosacral anorectal magnetic stimulation test was performed by using an anorectal probe with 4 ring electrodes and magnetic coil, and by stimulating bilateral lumbar and sacral plexuses, uses and recording 8 motor-evoked potentials at anal and rectal sites. MAIN OUTCOME MEASURES: The prevalence of lumbar and/or sacral neuropathy was examined. Secondary outcomes were correlation of neuropathy with anorectal sensorimotor function(s) and morphological changes. RESULTS: We evaluated 220 patients: 144 with fecal incontinence, 76 with mixed fecal incontinence/constipation, and 31 healthy controls. All 8 lumbar and sacral motor-evoked potential latencies were significantly prolonged (p < 0.01) in fecal incontinence and mixed fecal incontinence/constipation groups compared with controls. Neuropathy was patchy and involved 4.0 (3.0) (median (interquartile range)) sites. Lumbar neuropathy was seen in 29% to 65% of the patients in the fecal incontinence group and 22% to 61% of the patients in the mixed fecal incontinence/constipation group, and sacral neuropathy was seen in 24% to 64% and 29% to 61% of these patients. Anal neuropathy was significantly more (p < 0.001) prevalent than rectal neuropathy in both groups. There was no correlation between motor-evoked potential latencies and anal sphincter pressures, rectal sensation, or anal sphincter defects. LIMITATIONS: No comparative analysis with electromyography was performed. CONCLUSION: Lumbar or sacral plexus neuropathy was detected in 40% to 75% of patients with fecal incontinence with a 2-fold greater prevalence at the anal region than the rectum. Lumbosacral neuropathy appears to be an independent mechanism in the pathogenesis of fecal incontinence, unassociated with other sensorimotor dysfunctions. Translumbosacral anorectal magnetic stimulation has a high yield and is a safe and clinically useful neurophysiological test. See Video Abstract at http://links.lww.com/DCR/B728. PRUEBA DE ESTIMULACIN MAGNTICA TRANSLUMBOSACRAL ANORECTAL PARA LA INCONTINENCIA FECAL: ANTECEDENTES:La neuropatía puede causar incontinencia fecal y una combinación de incontinencia fe-cal/estreñimiento, pero su prevalencia no está clara, en parte debido a la falta de pruebas comple-tas de inervación espino-anorrectal.OBJETIVO:Desarrollar y determinar la utilidad clínica de una nueva prueba, estimulación magnética trans-lumbosacral anorrectal para la incontinencia fecal.DISEÑO:Estudio de cohorte observacional del 2012 al 2018.ENTORNO CLINICO:Centro de referencia terciario.PACIENTES:Pacientes con incontinencia fecal, combinación de incontinencia fecal/estreñimiento y controles sanos.INTERVENCIONES:Se realizó una prueba de estimulación magnética translumbosacral anorrectal utilizando una sonda anorrectal con 4 electrodos anulares y bobina magnética, y estimulando los plexos lumbares y sacros bilaterales y registrando ocho potenciales evocados motores las regiones anal y rectal.PRINCIPALES MEDIDAS DE RESULTADO:Se examinó la prevalencia de neuropatía lumbar y/o sacra. Los resultados secundarios fueron la correlación de la neuropatía con las funciones sensitivomotoras anorrectales y cambios morfológi-cos.RESULTADOS:Evaluamos 220 pacientes, 144 con incontinencia fecal, 76 con combinación de incontinencia fe-cal/estreñimiento y 31 sujetos sanos. Las ocho latencias de los potenciales evocadas motoras lum-bares y sacras se prolongaron significativamente (p <0,01) en la incontinencia fecal y el grupo mixto en comparación con los controles. La neuropatía fue irregular y afectaba 4,0 (3,0) (mediana (rango intercuartílico) sitios. Se observó neuropatía lumbar en 29-65% en la incontinencia fecal y 22-61% en el grupo mixto, y neuropatía sacra en 24-64% y 29-61 % de pacientes respectivamen-te. La neuropatía anal fue significativamente más prevalente (p <0,001) que la rectal en ambos grupos. No hubo correlación entre las latencias de los potenciales evocadas motoras y las presio-nes del esfínter anal, la sensación rectal o los defectos del esfínter anal.LIMITACIONES:Sin análisis comparativo con electromiografía.CONCLUSIÓNES:Se detectó neuropatía del plexo lumbar o sacro en el 40-75% de los pacientes con incontinencia fecal con una prevalencia dos veces mayor en la región anal que en el recto. La neuropatía lumbo-sacra parece ser un mecanismo independiente en la patogenia de la incontinencia fecal, no asocia-do con otras disfunciones sensitivomotoras. La estimulación magnética translumbosacral anorrec-tal tiene un alto rendimiento, es una prueba neurofisiológica segura y clínicamente útil. Consulte Video Resumen en http://links.lww.com/DCR/B728.

Organizing and Developing a GI Motility Lab in Community Practice: Challenges and Rewards.

PURPOSE OF REVIEW: Neurogastroenterology and motility is a rapidly evolving subspecialty that encompasses over 33% of gastroenterological disorders, and up to 50% of referrals to gastroenterology practice. It includes common problems such as dysphagia, gastroesophageal reflux disease, irritable bowel syndrome, chronic constipation, gastroparesis, functional dyspepsia, gas/bloating, small intestinal bacterial overgrowth, food intolerance and fecal incontinence Standard diagnostic tests such as endoscopy or imaging are normal in these conditions. To define the underlying mechanism(s)/etiology of these disorders, diagnostic motility tests are often required. These are best performed by well-trained personnel in a dedicated motility laboratory. Our purpose is to provide an up-to-date overview on how to organize and develop a motility laboratory based on our collective experiences in setting up such facilities in academia and community practice. RECENT FINDINGS: A lack of knowledge, training and facilities for providing diagnostic motility tests has led to suboptimal patient care. A motility laboratory is the hub for diagnostic and therapeutic motility procedures. Common procedures include esophageal function tests such as esophageal manometry and pH monitoring, anorectal function tests suchlike anorectal manometry, neurophysiology and balloon expulsion, dysbiosis and food intolerance tests such as hydrogen/methane breath tests, and gastrointestinal transit assessment. These tests provide an accurate diagnosis and guide clinical management including use of medications, biofeedback therapy, neuromodulation, behavioral therapies, evidence-based dietary interventions and endoscopic or surgical procedures. Further, there have been recent developments in billing and coding of motility procedures and training requirements that are not well known. This review provides a stepwise approach on how to set-up a motility laboratory in the community or academic practice and includes the rationale, infrastructure, staffing needs, commonly performed motility tests and their clinical utility, billing and coding strategies, training needs and economic considerations for setting up this service.