Irritable Bowel Syndrome With Constipation Patients Research Articles

Relationship Between Colonic Transit Response to Eating With Self-reported Constipation Severity in Constipated Patients According to the Phenotype.

Eating is the major synchronizer of gastrointestinal motility and secretions. The present study aims to evaluate the interplay between self-perceived constipation severity (CS) and colonic response to eating in constipated patients according to the phenotype. We included 387 consecutive outpatients complaining of Rome IV chronic idiopathic constipation. Likert scales for CS, abdominal pain severity, bloating severity, depression and anxiety assessment, total and segmental colonic transit time (CTT), and colonic transit response to eating (CTRE) were performed in all patients. Of the 387 patients included (49.7 ± 16.4 years), 320 (83%) were female, 203 had irritable bowel syndrome with constipation (IBS-C), 184 as functional constipation (FC), and 283 had defecation disorders (DD). The female gender was characterized by increased bloating severity (P = 0.011) and decreased Bristol stool form (P = 0.002). In IBS-C and FC patients, CS was related with bloating severity (P < 0.001 in both groups) and total CTT (P = 0.007 in IBS-constipation, P = 0.040 in FC). In IBS-C patients, CS was also associated with abdominal pain severity (P = 0.003) and Bristol stool form (P = 0.004). In contrast, in FC, CS was only related to left CTRE (P = 0.006), and in patients with DD, CS was associated with total CTT (P < 0.001) and left CTRE (P = 0.002). Colonic transit response to eating was not associated to CS in IBS-C patients, but left CTRE was associated with constipation severity in FC and DD patients.

The gut microbiota participates in the effect of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a multicenter, prospective, pre-post study

BackgroundInterindividual variation characterizes the relief experienced by constipation-predominant irritable bowel syndrome (IBS-C) patients following linaclotide treatment. Complex bidirectional interactions occur between the gut microbiota and various clinical drugs. To date, no established evidence has elucidated the interactions between the gut microbiota and linaclotide. We aimed to explore the impact of linaclotide on the gut microbiota and identify critical bacterial genera that might participate in linaclotide efficacy.MethodsIBS-C patients were administered a daily linaclotide dose of 290 µg over six weeks, and their symptoms were then recorded during a four-week posttreatment observational period. Pre- and posttreatment fecal samples were collected for 16S rRNA sequencing to assess alterations in the gut microbiota composition. Additionally, targeted metabolomics analysis was performed for the measurement of short-chain fatty acid (SCFA) concentrations.ResultsApproximately 43.3% of patients met the FDA responder endpoint after taking linaclotide for 6 weeks, and 85% of patients reported some relief from abdominal pain and constipation. Linaclotide considerably modified the gut microbiome and SCFA metabolism. Notably, the higher efficacy of linaclotide was associated with enrichment of the Blautia genus, and the abundance of Blautia after linaclotide treatment was higher than that in healthy volunteers. Intriguingly, a positive correlation was found for the Blautia abundance and SCFA concentrations with improvements in clinical symptoms among IBS-C patients.ConclusionThe gut microbiota, especially the genus Blautia, may serve as a significant predictive microbe for symptom relief in IBS-C patients receiving linaclotide treatment.Trial registration: This trial was registered with the Chinese Clinical Trial Registry (Chictr.org.cn, ChiCTR1900027934).

Tenapanor in the Treatment of Irritable Bowel Syndrome with Constipation: Discovery, Efficacy, and Role in Management.

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction (DGBI). IBS significantly impacts the quality of life of patients. Since its pathogenesis is unclear and can be multifactorial, it highlights the need for new and improved pharmaceutical drugs that not only improve bowel symptoms, but also address global IBS symptoms, such as abdominal pain. Tenapanor, a recently Food & Drug Administration (FDA)-approved medication for IBS with constipation (IBS-C), is a small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) that inhibits the absorption of sodium and phosphate in the gastrointestinal tract, resulting in fluid retention and softer stool. Furthermore, tenapanor reduces intestinal permeability to improve visceral hypersensitivity and abdominal pain. Due to its recent approval, tenapanor was not included in the recent IBS guidelines, however, it may be considered for IBS-C patients failing first-line treatment of soluble fiber. In this review article, we aim to provide in-depth information to the reader regarding the design of tenapanor, its development through Phase I, II and III randomized clinical trials, and its role in the treatment of IBS-C.

S567 Disease Burden and Care-Seeking Behavior of Patients With Irritable Bowel Syndrome With Constipation (IBS-C) in the United States

Introduction: Symptoms of IBS-C impose a significant negative burden to patients and the healthcare system. Our study examined disease burden and care-seeking behavior of patients with IBS-C. Methods: A cross-sectional, on-line health survey collected data on US adults from 8/2020-12/2021. IBS-C patients were defined using Rome IV criteria and matched 1:1 by sex, age, race, region and Charlson Comorbidity Index score to the general population. Outcomes comparing IBS-C patients to controls included an anxiety/depression screener, health-related quality of life (HRQoL) and productivity. Means were compared with ANOVA; proportions with chi-square tests. Endpoints assessed descriptively for IBS-C patients were care, treatment, symptom burden and satisfaction with control, health care provider management, and treatment. Results: Of 29,359 participants, 3.3% (956) met Rome IV criteria for IBS-C. Matching resulted in 910 patients and 910 controls. Most patients were female (76.9%), White (82.2%), with a mean age of 41.2 years. IBS-C patients had significantly higher proportions of moderate to severe anxiety and depression (p < .001) and significantly lower HRQoL vs controls (p < .001). Health impact on work productivity and daily activity was significantly worse among IBS-C patients vs controls (Table). Of IBS-C patients, 92.4% sought medical care for symptoms; 59.6% within the past year. 97.3% of IBS-C patients experienced ≥1 symptoms in the past 7 days. Abdominal discomfort was the symptom most experienced (71.0%); abdominal pain was the most bothersome (34.0%). Of the IBS-C patients that visited an ER or were hospitalized in the past 12-months due to bowel movement or abdominal symptoms, abdominal pain was the most common reason (90%). 74.2% reported currently taking an Rx and/or an OTC for their symptoms (12.6% Rx alone, 14.7% Rx and OTC, and 46.8% OTC alone). IBS-C patients were more dissatisfied than satisfied with control of bowel (47.4% vs 27.3%) and abdominal (45.9% vs 27.8%) symptoms. Those currently taking an Rx with or without an OTC were more satisfied with the control of bowel (42.6% vs 22.5%) and abdominal (46.6% vs 20.9%) symptoms than those taking only an OTC (Figure). Conclusion: New data from a large survey study demonstrates that there remains a considerable disease burden and unmet need for IBS-C patients, many of whom commonly experience pain and discomfort and are dissatisfied with their symptom control. This highlights the need to better address the multiple symptoms of IBS-C.Figure 1.: Satisfaction with Control, HCP Management and Treatment Table 1. - Rome IV IBS-C Cohort vs Control Comparisons (1) Question fielded 12/20-12/21; cohort n=687 and control n=556. (2) GAD-7: Generalized Anxiety Disorder, 7-item; range: 0-21. (3) PHQ-9: Patient Health Questionnaire, 9-item; range 0-29. (4) Question fielded 12/20-12/21; cohort n=387 and control n=340 Rome IV IBS-C Cohort (N=910) Control(N=910) Sig. Female 76.9% 76.9% 1.000 Age, mean (SD) 41.2 (14.9) 41.2 (14.9) 0.995 Black or African American 9.3% 9.3% 1.000 White 82.2% 82.2% Other 8.5% 8.5% Proportion of Hispanic, Latino or Spanish origin 8.6% 10.2% 0.296 Northeast 16.5% 16.5% 1.000 Midwest 24.7% 24.7% South 39.7% 39.7% West 19.1% 19.1% Charlson Comorbidity Index (CCI) score, mean (SD) 0.5 (1.0) 0.5 (1.0) 1.000 Body Mass Index (BMI) (lbs/in2), mean (SD) 27.2 (7.3) 28.0 (7.3) 0.033 Proportion employed per Work Productivity and Impairment (WPAI) (1) 56.3% 61.2% 0.086 Proportion educated more than high school 75.5% 72.2% 0.110 Mean household income (Census derived from zip code), mean (SD) 64,553(26,853) 64,629(25,910) 0.951 Anxiety (GAD-7)[2]) score, mean (SD) 9.1 (6.1) 6.6 (6.0) < 0.001 Depression (PHQ-9 [3]) score, mean (SD) 10.9 (7.3) 7.9 (7.4) < 0.001 Chronic Pain 60.4% 39.6% < 0.001 Migraine 60.2% 39.8% < 0.001 Insomnia 67.1% 32.9% < 0.001 GERD 74.6% 25.4% < 0.001 VR-12 Mental Component Summary (MCS), mean (SD) 38.0 (12.5) 44.5 (12.2) < 0.001 VR-12 Physical Component Summary (PCS), mean (SD) 41.2 (10.7) 45.6 (10.3) < 0.001 VR-12 Health utility (VR-6D), mean (SD) 0.61 (0.11) 0.68 (0.12) < 0.001 Health problems affected work productivity rating (0-10 scale), mean, SD (4) 2.8 (2.7) 1.8 (2.8) < 0.001 Health problems affected daily activities rating (0-10 scale), mean, SD (1) 3.8 (3.1) 2.4 (3.1) < 0.001

Virtual Tai Chi program for patients with irritable bowel syndrome with constipation: Proof-of-concept feasibility trial.

Satisfaction with current treatment options for irritable bowel syndrome with constipation (IBS-C) is low, with many patients turning to complementary treatments. Tai Chi is a mind-body medicine practice with proven efficacy in other functional disorders. As a proof-of-concept, we tested the feasibility and preliminary clinical outcomes associated with a Tai Chi program designed for IBS-C. A total of 27 IBS-C patients participated in a single-arm trial of 8 sessions of Tai Chi delivered weekly over 7 weeks via live videoconferencing in group format. Clinical improvement was assessed via change in IBS Symptom Severity Score (IBS-SSS) from baseline to 4 weeks posttreatment (week 11) with secondary outcomes exploring symptom ratings, IBS-related quality of life (IBS-QOL), GI-specific anxiety, abdominal distention, and psychological factors. Despite substantial dropout (n=7; 26%), the treatment protocol had moderate to excellent feasibility for other criteria. Treatment satisfaction was excellent. Exit interviews confirmed high satisfaction with the program among completers, but a high burden of data collection was noted. One participant experienced an adverse event (mild, exacerbation of sciatica). There was a significant improvement in intra-individual IBS-SSS between baseline and posttreatment (average change -66.5, 95% CI -118.6 to -14.3, p=0.01). Secondary outcomes were notable for improvements in other IBS symptom scoring measures, IBS-QOL, measured abdominal diameter, and leg strength. Our data provide preliminary evidence of the feasibility of a Tai Chi intervention for IBS-C, show promise for improving outcomes, and identify more streamlined data collection as an area for further program improvement.

Cost-Effectiveness of Linaclotide Compared to Osmotic Laxatives in the Treatment of Irritable Bowel Syndrome with Constipation in China.

Linaclotide, a selective agonist of guanylate cyclase C, was highly recommended for the treatment of irritable bowel syndrome with constipation (IBS-C). However, the cost-effectiveness of linaclotide in Chinese is not known, and this study aimed to assess the cost-effectiveness of linaclotide for patients with IBS-C. An economic evaluation was conducted with a Markov model from a societal perspective. The Markov model was structured to simulate the discontinuation and continuation of medication in IBS-C patients in clinical practice, as well as the revisit and non-visit of non-responding patients. The cycle of the model was 4weeks, and the time horizon was 1year. The efficacy data in the model was from the risk ratios obtained by the meta-analysis and the calculation of the response rate of the three medications. The utility, discontinuation rate of the medication, and revisit rate data were from published literature, while the cost data were obtained from experts' opinions and published literature. A series of sensitivity analyses was performed on parameters potentially having impact on the model outputs. The QALYs (quality-adjusted life years) gained for 1-year treatment with linaclotide, polyethylene glycol, and lactulose were 0.821, 0.795, and 0.781, respectively. The corresponding total costs were CNY 7,721 (USD 1,120), CNY 8,797 (USD 1,276) and CNY 9,481 (USD 1,375). In both comparisons, linaclotide was dominant. Compared with polyethylene glycol and lactulose, the likelihood of linaclotide being cost-effective was 100% for both, using 1 times per capita GDP per QALY as willingness-to-pay threshold. IBS-C seriously affects the quality of life of patients with IBS-C, and linaclotide can improve symptoms and quality of life at less cost.

S0492 Tegaserod 6 Mg BID for Treating Abdominal Pain and Bloating in Women With Irritable Bowel Syndrome With Constipation but Without Cardiovascular Risk Factors: A Pooled Analysis of 4 Clinical Trials

INTRODUCTION: Irritable bowel syndrome with constipation (IBS-C) is characterized by symptoms that extend beyond bowel movement frequency and are worrisome to most patients (e.g., abdominal pain, bloating). The 5-HT4 receptor agonist tegaserod 6 mg BID is approved for treating IBS-C in women <65 years of age without cardiovascular disease (CVD) histories. METHODS: These pooled analyses evaluated tegaserod 6 mg BID using data from four, 12-week, randomized, placebo-controlled trials in IBS-C patients with ≥3-month symptom histories. Consistent with the indicated population, these analyses primarily focused on women <65 years without CVD histories. The outcomes of interest were key secondary endpoints, including proportions of patients experiencing complete, considerable, and somewhat IBS symptom relief, and abdominal pain/discomfort, bloating, and bowel movement treatment response (≥2 point improvement on a 7-point Likert scale) in ≥50% of patients over 12 weeks. Differences in treatment response rates and odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated using Cochran-Mantel-Haenszel estimates controlling for investigator site. RESULTS: Among the analysis population (tegaserod: n = 1122; placebo: n = 1079), 99.7% was aged <65 years. Mean ages were 38.2–40.1 years and duration of IBS symptoms was ∼15 years. At the end of 12 weeks, a significantly higher proportion of patients experienced IBS symptom relief (tegaserod: 67.3%; placebo: 58.2%; difference [95% CI]: 8.2% [3.4–13.1]; P ≤ .001). The OR (95% CI) for achieving IBS symptom relief was 1.43 (1.16–1.76); P < .001. At 12 weeks, a significantly higher proportion of patients also met response criteria for bloating (tegaserod: 21.8%; placebo: 15.6%; difference [95% CI]: 6.0% [2.9–9.2]; P < .001), abdominal pain/discomfort (tegaserod: 22.9%; placebo: 17.5%; difference [95% CI]: 5.2% [1.9–8.4]; P = .002), and bowel movements (tegaserod: 49.7%; placebo: 33.1%; difference [95% CI]: 16.2% [12.1–20.3]; P < .001). The OR (95% CI) for achieving response on bloating (1.54 [1.23–1.93]), abdominal pain/discomfort (1.43 [1.14–1.78]), and bowel movements (1.99 [1.67–2.38]) were statistically significant in favor of tegaserod 6 mg BID (P < 0.001). CONCLUSION: Based on these pooled analyses, tegaserod 6 mg BID significantly improved the core symptoms of IBS-C, including bloating, abdominal pain/discomfort, and bowel movement frequency in women <65 years of age without CVD histories.Figure 1.: Bloating and abdominal pain/discomfort and bloating improved with tegaserod 6 mg BID compared to placebo in treating women with IBS-C. Response was defined as a ≥2 point improvement on a 7-point Likert scale.

Circulating neurotransmitter levels in irritable bowel syndrome: correlation of laboratory tests and clinical findings

Objective: to estimate blood levels of serotonin and melatonin neurotransmitters in patients with irritable bowel syndrome and to evaluate the role of neurohumoral imbalance in the development and clinical manifestations of irritable bowel syndrome phenotypes.Materials and methods: the study included 60 patients (range, 18 – 45 years) diagnosed with irritable bowel syndrome according to the Roman IV criteria for irritable bowel syndrome (2016). 20 patients with a confirmed diagnosis of ulcerative colitis (UC) were assigned to a comparison group. The control group was composed of 45 apparently healthy subjects. All subjects were assigned to subgroups based on the prominent clinical presentation: irritable bowel syndrome with constipation (IBS-C), irritable bowel syndrome with diarrhea (IBS-D) and mixed irritable bowel syndrome (IBS-M). In addition to all the necessary procedures (clinical, laboratory and instrumental), blood concentrations of endogenous serotonin and melatonin were measured using enzyme-linked immunosorbent assay (ELISA).Results: the concentrations of endogenous serotonin and melatonin were significantly lower in patients with irritable bowel syndrome as compared with those having ulcerative colitis or healthy individuals. The detection rates of lowering serotonin levels were 53.3 % and 65 % — for melatonin. Low levels of melatonin were detected both in IBS-D and IBS-C patients. 69.57 % of IBS-D patients had elevated levels of serotonin as compared with the reference values for healthy subjects. We found a strong correlation between the severity of bloating and abdominal pain on the one hand, and low levels of endogenous serotonin and melatonin, on the other hand.Conclusion: our findings suggest that serotonin and melatonin neurotransmitters play a significant role in the pathophysiology and clinical manifestations of estimate blood levels of serotonin and melatonin neurotransmitters in patients with irritable bowel syndrome.

Psychometric Analysis of the Abdominal Score From the Diary for Irritable Bowel Syndrome Symptoms–Constipation Using Phase IIb Clinical Trial Data

ObjectivesThe Diary for Irritable Bowel Syndrome Symptoms–Constipation (DIBSS-C) has been developed to assess the core signs and symptoms of irritable bowel syndrome with constipation (IBS-C). This article presents the psychometric evaluation of the DIBSS-C abdominal score. MethodsData for these analyses are from a multicenter phase IIb study in IBS-C patients (NCT02559206). Subjects completed a number of assessments via handheld electronic diary throughout the study. The analyses used the intent-to-treat population and were blinded to randomized treatment group. The analyses evaluated the reliability, validity, and responsiveness of the DIBSS-C abdominal score; identified an appropriate scoring algorithm; and determined thresholds for interpreting clinically meaningful changes at the individual level. ResultsThe correlations between the DIBSS-C abdominal symptom items (ie, abdominal pain, discomfort, and bloating) were strong (>0.75). Cronbach’s alpha for the abdominal symptom severity items was very strong (.94), indicating that the 3 abdominal symptom items produce a reliable score. The intraclass correlation coefficient for the abdominal score was 0.82, exceeding the threshold of 0.70 and indicating good test–retest reliability. Guyatt’s responsiveness statistic values all exceeded the threshold for a large effect of 0.80, so the DIBSS-C abdominal score can be considered highly responsive to change. Triangulation across 3 sets of anchor-based analyses indicated that a threshold of −2.0 points on the abdominal score is an appropriate threshold for identifying meaningful change. ConclusionsOverall, this study provides evidence that the DIBSS-C abdominal score is valid, reliable, responsive to change, and interpretable for assessing treatment benefit in patients with IBS-C.

Pelvic Floor Symptom Related Distress in Chronic Constipation Correlates With a Diagnosis of Irritable Bowel Syndrome With Constipation and Constipation Severity but Not Pelvic Floor Dyssynergia.

Background/AimsAlthough symptoms related to the pelvic floor, such as pelvic organ prolapse (POP) and lower urinary tract symptoms (LUTS), are common in patients with chronic constipation (CC), its impact is not clear. Our aims were to investigate the following (1) compare pelvic floor symptom related dysfunction in irritable bowel syndrome with constipation (IBS-C) and functional constipation (FC), and (2) symptom correlation with findings on anorectal manometry (ARM) and balloon expulsion test.MethodsThis was a retrospective analysis of patients with CC undergoing ARM. IBS-C and FC were diagnosed by Rome III criteria. Pelvic Floor Distress Inventory (PFDI-20) was used to measure pelvic floor symptom distress. Constipation Severity Scale was used to assess constipation severity.ResultsA total of 107 patients underwent ARM (64 FC, 43 IBS-C). The overall PFDI-20 score in IBS-C was higher compared with FC patients (118.0 vs 79.2, P = 0.001). In those with IBS-C, POP, LUTS, and colorectal symptoms subscales were all higher compared with FC patients (P < 0.05 for each). On multivariable regression, IBS-C (P = 0.001) and higher constipation severity (P = 0.001) were both independently associated with higher PFDI scores. ARM parameters and abnormal balloon expulsion test did not correlate with PFDI scores.ConclusionsCompared with FC patients, those with IBS-C have significantly higher distress from pelvic floor specific symptoms including POP and LUTS. Higher abdominal pain among IBS-C patients did not entirely explain these findings. A diagnosis of IBS-C and higher constipation severity correlated with PFDI-20 scores, but dyssynergia did not.

Influence of the requirement for abdominal pain in the diagnosis of irritable bowel syndrome with constipation (IBS-C) under the Rome IV criteria using data from a large Japanese population-based internet survey

BackgroundRome III was revised to Rome IV in May 2016. One important change in the Rome IV criteria is that abdominal pain must be present for a diagnosis of irritable bowel syndrome (IBS). Under Rome III, in contrast, patients with abdominal discomfort only could be diagnosed with IBS, but these cases under Rome IV are now classified as unspecified functional bowel disorder (FBD). In a simple comparison of Rome III and Rome IV, it is unclear whether this difference reflects the influence of symptomatic frequency or the presence of abdominal pain. In particular, the influence of abdominal pain restriction on the diagnosis of IBS with predominant constipation (IBS-C) in the Rome IV criteria is largely unknown.MethodsWe reclassified subjects from a Japanese internet survey experiencing abdominal pain or discomfort at least one day each week as surrogate Rome III IBS-C subjects. Among them, we then reclassified subjects experiencing abdominal pain as surrogate Rome IV IBS-C subjects and subjects not experiencing abdominal pain as surrogate Rome IV FBD subjects. Symptoms were quantified and compared between the two groups.ResultsThe surrogate Rome IV IBS-C subjects felt a significantly higher degree of anxiety in their daily lives (p < 0.001) compared with the surrogate Rome IV FBD subjects. The combined female and 20–49 years surrogate Rome IV IBS-C subjects felt a higher degree of anxiety in their daily lives (p < 0.05) than the respective Rome IV FBD subjects.ConclusionsThese results suggest that female IBS-C patients aged 20–49 years with abdominal pain in Rome IV have more anxiety than those without abdominal pain in Rome III. Changes in the diagnostic criteria from Rome III to Rome IV will better identify candidates for the biopsychosocial approach.Trial registrationAlthough this survey was an anonymous internet survey, we obtained informed consent for the study as an online response. The disclosure of this study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (approval number: 2015–1-405).

Evaluation of the Safety and Tolerability of Plecanatide in CIC and IBS-C Patients Aged 65 and Older

Introduction: Constipation, including Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C), is prevalent in patients aged 65 and older. Currently, there is limited clinical trial safety/tolerability data in older adults. Recently, two CIC and two IBS-C trials with plecanatide were completed which represent the largest Phase 3 trials to date in each of these disorders. All of these trials permitted enrollment of eligible patients up to the age of 80 and 85, respectively. Rome IV supports the concept of CIC and IBS-C as a spectrum of disorders with overlapping symptoms. This suggests that combining the safety populations from these studies would be acceptable and provide for a larger cohort of patients. Therefore, the aim of this study was to perform a safety analysis of plecanatide in patients ≥65 years old. Methods: Safety populations from 4 large Phase 3 trials (2 CIC, 2 IBS-C) were combined for a post-hoc analysis. Patients enrolled in these trials met modified Rome III criteria for CIC and IBS-C, respectively. Upon completion of the two-week baseline period, patients were randomized to either plecanatide 3mg or placebo (pbo). Medication was taken once daily with or without food. Safety assessments were conducted by the collection of spontaneously reported adverse events (AEs) and responses to open ended non-specific questions. AE rates were compared between those patients ≥65 and those <65 using descriptive statistics to assess for increased safety risks to an older population. Results: For those ≥65 years there were 151 plecanatide and 166 pbo patients. For those 2% and >pbo were headache and arthralgia each at 2.6% for the ≥65 group. The overall discontinuation rates and the discontinuation rates due to diarrhea were similar among the two age groups (Table). Conclusion: In these four trials for plecanatide, a meaningful number of patients ≥65 were enrolled. The analysis of the safety data indicates similar AE rates and discontinuation rates for patients ≥65 compared to those <65. These data indicate plecanatide is safe and well tolerated in both groups of patients.427 Figure 1 No Caption available.

Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis.

Linaclotide and plecanatide are guanylate cyclase-C (GCC) agonists for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Our objective is to evaluate the efficacy and tolerability of GCC agonists based on data from multiple randomized controlled trials (RCTs). We searched PubMED, EMBASE, Cochrane databases, clinicaltrials.gov, major conference abstracts, Food and Drug Administration (FDA) websites, and United States Securities and Exchange Commission filings of drug sponsors to identify RCTs of CIC or IBS-C patients. We assessed efficacy based on FDA-approved composite responder endpoints, diarrhea as an adverse event, and study withdrawal owing to diarrhea for each therapy. Trial results were pooled using DerSimonian and Laird random effects model of meta-analysis and exact logistic regression when appropriate with 95% confidence intervals. Meta-regression was performed to compare outcomes between therapies adjusting for placebo event rate. Eight linaclotide trials (five CIC; three IBS-C) and seven plecanatide trials (four CIC; three IBS-C) evaluating 10,369 patients met inclusion criteria. FDA publications documented that different definitions for diarrhea were used in linaclotide vs. plecanatide trials. Both drugs were efficacious in treating CIC (linaclotide 72 μg (Odds ratio (OR)=3.11, 95% CI 1.81-5.34); linaclotide 145 μg (OR=3.25, 2.15-4.91); plecanatide 3 mg (OR=1.99, 1.57-2.51)) and IBS-C (linaclotide 290 μg (OR=2.43, 1.48-3.98); plecanatide 3 mg (OR=1.87, 1.47-2.38); plecanatide 6 mg (OR=1.92, 1.48-2.48)). Diarrhea occurred in excess of placebo in treating CIC (linaclotide 72 μg (OR=3.07, 1.97-4.77); linaclotide 145 μg (OR=3.70, 2.69-5.10); plecanatide 3 mg (OR=3.86, 1.83-8.12)) and IBS-C (linaclotide 290 μg (OR=8.02, 5.20-12.37); plecanatide 3 mg (OR=5.55, 1.62-19.00); plecanatide 6 mg (OR=4.13, 1.57-10.83)). Based on meta-regression, there were no statistically significant differences between therapies in odds ratios for efficacy, diarrhea, or diarrhea-related study withdrawals. Both linaclotide and plecanatide demonstrate similar efficacy and tolerability in treating IBS-C and CIC. No differences in odds of diarrhea were seen between linaclotide and plecanatide.

Effect of Linaclotide DR1, a Delayed-Release Formulation of Linaclotide, in IBS-C Patients: Analysis of Symptom Improvement Using Responder Radar Plots

Introduction: Linaclotide (LIN) is a guanylate cyclase-C agonist approved as an immediate-release (IR) formulation for irritable bowel syndrome with constipation (IBS-C). A LIN delayed-release (DR) formulation, DR1, was developed with the hypothesis that targeting the ileal region would increase abdominal pain relief and cause less fluid secretion. A Phase 2b dose-ranging study in IBS-C patients showed that a 300μg dose of LIN DR1 improved abdominal and bowel symptoms with an acceptable safety profile. This analysis aims to further examine symptom improvement in that study using responder radar plots, with a focus on LIN DR1 300μg (planned Phase 3 dose), LIN IR, and placebo (PBO). Methods: IBS-C patients meeting Rome III IBS criteria and baseline symptom requirements were randomized to 1 of 8 groups; this analysis includes the 199 patients in the PBO, LIN IR 290μg, and LIN DR1 300μg groups. Patients reported abdominal/bowel symptoms daily and adequate relief (yes/no) weekly during 2-week baseline (BL) and 12-week treatment periods. Change-from-BL and responder endpoints (abdominal pain [≥30% decrease from BL], CSBM+1 [increase of ≥1 complete spontaneous bowel movement from BL], APC+1 [both abdominal pain and CSBM+1 in the same week], and adequate relief, each for ≥6/12 weeks and ≥9/12 weeks) were analyzed. Results: Improvements from BL in abdominal pain, abdominal discomfort, spontaneous bowel movement (SBM) frequency, straining, and stool consistency were seen for DR1 vs PBO (nominal P<0.05); numerical improvements vs PBO were seen for other symptoms (Table). Changes from BL were generally similar in the DR1 and IR groups. 6/12 week responder rates were higher in DR1 vs PBO patients (nominal P<0.05) for APC+1, CSBM+1, and adequate relief; and numerically higher for abdominal pain (P=0.053; Figure). DR1 responder rates were numerically higher vs IR for APC+1, abdominal pain, and adequate relief, and similar for CSBM+1 (Figure). More stringent 9/12 week responder endpoints showed abdominal pain and adequate relief improvement for DR1 vs PBO (nominal P<0.05) and numerical improvement in abdominal pain vs IR (Figure). Diarrhea, the most common AE, led to discontinuation in 3%, 6%, and 0% of DR1, IR, and PBO patients, respectively.FigureTable: Table. Change from Baseline in Abdominal and Bowel SymptomsConclusion: Targeted LIN delivery with DR1 300μg appears to maintain constipation relief and may enhance benefit for abdominal pain and abdominal discomfort in IBS-C patients. Further study is warranted to confirm these results.

The BURDEN IBS-C Study (Better Understanding and Recognition of the Disconnects, Experiences, and Needs of Patients With Irritable Bowel Syndrome With Constipation)

Introduction: Irritable bowel syndrome with constipation (IBS-C) is a common gastrointestinal disorder, with limited literature on patients' experiences. The BURDEN IBS-C Study was designed to develop a better understanding of the experiences, attitudes, and unmet needs of patients with IBS-C and to assess the understandings of the healthcare professionals (HCPs) who treat these patients. Methods: BURDEN IBS-C utilized proprietary databases to identify IBS-C patients, who then participated in an author-developed, IRB-approved online survey. HCPs who treat IBS-C patients were recruited and participated in a separate online survey. Results: Over 1300 IBS-C patients completed the survey (mean age 46 yrs; 73% female; 65% white). Patients most commonly reported feeling frustrated (43%), accepting (39%), stressed (28%), and self-conscious (22%) regarding their IBS-C, with 60% describing symptoms as somewhat to extremely bothersome. HCPs (N=331) agreed that patients were frustrated (76%) and stressed (65%); however, HCPs were less likely to recognize patients are accepting (13%) of IBS-C (vs 39% of patients) and are more likely to believe patients are obsessed with symptoms (48% vs 8% of patients). On average, productivity (work/school) was impacted 4 days/month, with absenteeism occurring ˜1.5 days/month. Personal activity was impacted 3 days/month. Satisfaction regarding prescription (Rx) IBS-C treatments was assessed. Non-Rx IBS-C treatments were being used by 76% of patients, with only 9% of patients currently taking an Rx treatment for their IBS-C symptoms. Of patients currently using an Rx IBS-C treatment, 78% were not completely satisfied, primarily due to lack of efficacy (51%). Symptoms experienced despite Rx treatment included bloating/distension (57%), abdominal discomfort (43%), hard/lumpy stools (34%), and feeling of incomplete evacuation (31%). Only 21% of HCPs were satisfied or completely satisfied with current Rx IBS-C treatments, citing inadequate efficacy (55%) and diarrhea (41%) as challenges most frequently experienced in treating IBS-C. Conclusion: BURDEN IBS-C confirmed the physical, psychosocial, and clinical impact of IBS-C, indicating that IBS-C has a substantial burden on quality of life. Patients and HCPs felt current treatments were not sufficient in addressing IBS-C symptomatology. Attitudinal disconnects, namely symptom obsession and disease acceptance, were uncovered regarding the impact and experience of IBS-C.

Impact of Stool Consistency on Bowel Movement Satisfaction in IBS-C or CIC Patients Treated With Linaclotide or Other Medications: Results From the CONTOR Study

Introduction: Medications for constipation can cause loose or watery stools (LoWS). As new medications become available, an understanding of patients' perceptions regarding treatment effects and satisfaction may help clinicians manage patients' expectations and inform clinical perspectives of these treatments. Linaclotide is one of several treatment options for irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC); however, little information is available on the impact of stool consistency on patient-reported bowel movement (BM) satisfaction associated with their treatment options. Methods: Data were derived from CONTOR, a longitudinal research platform combining administrative claims and patient survey data for IBS-C and CIC patients [1]. Pooled data from two patient-reported 7-day daily diaries completed at baseline and Month 12 were used to create a dataset of 2907 diaries representing 26,524 BMs for 1830 patients to understand factors influencing BM satisfaction, particularly among patients taking linaclotide. Data included bowel/abdominal symptom treatments taken in the prior 24 hours, time and 1-word description of each BM, and whether the BM was satisfactory. Binary variables were created for: medication use in the past 24 hours and categorization of the BM as LoWS (based on Bristol Stool Form Scale [BSFS] 6/7), hard or lumpy stool (HoLS, based on BSFS 1/2), or neither LoWS nor HoLS. Logistic regressions between linaclotide and LoWS analyzed the relationship between BM satisfaction and treatment. Results: Overall, BMs characterized as HoLS were satisfactory less often (19.4%) than LoWS (51.2%) and neither LoWS nor HoLS (61.2%). Patients taking linaclotide reported a similar proportion of BMs as satisfactory when described as LoWS (65.6%) or as neither LoWS nor HoLS (64.1%) [Figure]. Patients reporting linaclotide use had higher odds of reporting BMs as satisfactory (odds ratio [OR] 1.23, P<0.05) than those who had not; the odds were even greater among linaclotide users with LoWS (OR 2.05, P<0.001) when considering whether the impact of linaclotide on satisfaction depended on stool form [Table].FigureTable: Table. Model ResultsConclusion: Patients were more likely to report BMs as satisfactory for stools described as LoWS or neither LoWS nor HoLS. Compared to those not taking linaclotide, patients taking linaclotide were more likely to be satisfied, particularly those reporting LoWS.

Constipation Symptoms Differ Between Individuals With Irritable Bowel Syndrome With Constipation and Chronic Idiopathic Constipation

Introduction: We characterized constipation symptoms among individuals with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). Methods: Adults (>18 years of age) were identified from a nationwide sample of over 70,000 US adults meeting modified Rome III criteria for IBS-C or CIC. Dimensions of the constipation experience were assessed using the validated GI-PROMIS® questionnaire administered by the novel ehealth app MyGI-Health. Question items were developed using systematic literature review followed by open-ended questions in patient focus groups. Question items were mapped onto a matrix according to pre-defined dimensions within the conceptual framework of constipation symptoms. Content validity, patient understanding, and reliability were established in semistructured interviews and a subsequent multi-center survey. Odds ratios (OR) with 95% confidence intervals (CI) were calculated using logistic regression to evaluate responses in IBS-C relative to CIC which were previously mapped onto five-point response scales. Differences in GI-PROMIS scores (range=0-100, mean=50, standard deviation=10) were assessed using one-way ANOVA. Results: 970 individuals met eligibility criteria (275 with IBS-C; 734 with CIC). Demographics were similar except for education, marital status, employment status, and income. GI-PROMIS scores, as a composite measure of frequency and severity, were higher in IBS-C (score=75) compared to CIC (score=68) (p=0.01). Among first-order individual question items within the constipation symptom domain, there were differences in constipation symptoms reported by IBS-C and CIC. IBS-C patients had more hard or lumpy stools, rectal pain frequency, and need for digitation though overall bothersomeness was similar between the groups (Table). No items in the instrument favored more severe or frequent symptoms in the CIC cohort.Table: Table. Responses to constipation question items characterizing the constipation experience in IBS-C and CICConclusion: GI-PROMIS scores are higher in IBS-C compared to CIC individuals. Given the striking overlap between symptoms in patients with IBS-C and CIC, it is reasonable to hypothesize that IBS-C and CIC reside upon a spectrum of disease severity with CIC patients representing the less severely affected end of the spectrum and IBS-C representing the more severely affected end of the spectrum.

Chronic constipation diagnosis and treatment evaluation: the \u201cCHRO.CO.DI.T.E.\u201d study

BackgroundAccording to Rome criteria, chronic constipation (CC) includes functional constipation (FC) and irritable bowel syndrome with constipation (IBS-C). Some patients do not meet these criteria (No Rome Constipation, NRC). The aim of the study was is to evaluate the various clinical presentation and management of FC, IBS-C and NRC in Italy.MethodsDuring a 2-month period, 52 Italian gastroenterologists recorded clinical data of FC, IBS-C and NRC patients, using Bristol scale, PAC-SYM and PAC-QoL questionnaires. In addition, gastroenterologists were also asked to record whether the patients were clinically assessed for CC for the first time or were in follow up. Diagnostic tests and prescribed therapies were also recorded.ResultsEight hundred seventy-eight consecutive CC patients (706 F) were enrolled (FC 62.5%, IBS-C 31.3%, NRC 6.2%). PAC-SYM and PAC-QoL scores were higher in IBS-C than in FC and NRC. 49.5% were at their first gastroenterological evaluation for CC. In 48.5% CC duration was longer than 10 years. A specialist consultation was requested in 31.6%, more frequently in IBS-C than in NRC. Digital rectal examination was performed in only 56.4%. Diagnostic tests were prescribed to 80.0%. Faecal calprotectin, thyroid tests, celiac serology, breath tests were more frequently suggested in IBS-C and anorectal manometry in FC. More than 90% had at least one treatment suggested on chronic constipation, most frequently dietary changes, macrogol and fibers. Antispasmodics and psychotherapy were more frequently prescribed in IBS-C, prucalopride and pelvic floor rehabilitation in FC.ConclusionsPatients with IBS-C reported more severe symptoms and worse quality of life than FC and NRC. Digital rectal examination was often not performed but at least one diagnostic test was prescribed to most patients. Colonoscopy and blood tests were the “first line” diagnostic tools. Macrogol was the most prescribed laxative, and prucalopride and pelvic floor rehabilitation represented a “second line” approach. Diagnostic tests and prescribed therapies increased by increasing CC severity.

A case-control comparison of direct healthcare-provider medical costs of chronic idiopathic constipation and irritable bowel syndrome with constipation in a community-based cohort

Objective: Patients with constipation account for 3.1 million US physician visits a year, but care costs for patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) compared to the general public have received little study. The study aim was to describe healthcare utilization and compare medical costs for patients with IBS-C or CIC vs matched controls from a community-based sample.Methods: A nested case-control sample (IBS-C and CIC cases) and matched controls (1:2) for each case group were selected from Olmsted County, MN, individuals responding to a community-based survey of gastrointestinal symptoms (2008) who received healthcare from a participating Rochester Epidemiology Project (REP) provider. Using REP healthcare utilization data, unadjusted and adjusted standardized costs were compared for the 2- and 10-year periods prior to the survey for 115 IBS-C patients and 230 controls and 365 CIC patients and 730 controls. Two time periods were chosen as these conditions are episodic, but long-term.Results: Outpatient costs for IBS-C ($6,800) and CIC ($6,284) patients over a 2-year period prior to the survey were significantly higher than controls ($4,242 and $5,254, respectively) after adjusting for co-morbidities, age, and sex. IBS-C outpatient costs ($25,448) and emergency room costs ($6,892) were significantly higher than controls ($21,024 and $3,962, respectively) for the 10-year period prior. Unadjusted data analyses of cases compared to controls demonstrated significantly higher imaging costs for IBS-C cases and procedure costs for CIC cases over the 10-year period.Limitations: Data were collected from a random community sample primarily receiving care from a limited number of providers in that area.Conclusions: Patients with IBS-C and CIC had significantly higher outpatient costs for the 2-year period compared with controls. IBS-C patients also had higher ER costs than the general population.

Chronic Constipation and IBS-C Treatment and Outcomes Real World Research Platform (CONTOR): A Large, Longitudinal Observational Study

Introduction: CONTOR is a longitudinal, observational platform combining administrative claims and patient survey data to examine associations between symptoms, treatments, and outcomes among chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) patients. Our objective is to describe baseline characteristics of CIC and IBS-C patients participating in CONTOR. Methods: Fully-insured patients ≥18 years old were identified from a large, geographically-diverse US health plan based on claims from 12/2012-6/2015. Criteria included: ≥1 medical claim for constipation (564.0x), IBS (564.1x), or abdominal pain (789.0x), plus ≥1 pharmacy claim for a stool softener/laxative; or ≥1 claim for linaclotide or lubiprostone. At baseline, participants completed surveys including measures of general and disease-specific health-related quality of life (HRQOL) and symptom-specific work productivity and activity impairment, and assessments of symptom severity, treatment use and satisfaction, and 7-day daily diaries of treatments and symptoms. Data were collected over 12 months through quarterly surveys, monthly medication updates, and a 7-day daily diary at month 12; data presented are from the baseline survey and baseline diary. Results: Of 18,590 patients invited to participate, 2052 eligible respondents completed the baseline survey; 1747 completed the baseline diary. The majority were female; mean age was 47 years (Table). Respondent and non-respondent demographics did not differ meaningfully. Approximately 38% and 44% reported physician diagnoses of CIC and IBS-C, respectively. Nearly all reported experiencing bowel/abdominal symptoms for ≥2 years, with nearly half experiencing symptoms for >10 years. Almost three-quarters have been treated for bowel/abdominal symptoms for ≥2 years; probiotics, polyethylene glycol, and linaclotide were the most commonly reported treatments used in the last 7 days. Overall, respondents reported multiple bothersome abdominal and bowel symptoms as well as diminished HRQOL and work productivity due to their CIC/IBS-C. Conclusion: CONTOR, the first comprehensive, real-world longitudinal platform among CIC and IBS-C patients, illustrates the chronic symptom burden associated with these conditions. CONTOR participants reported lengthy and complex treatment histories with patients experiencing burdensome and disruptive symptoms for many years, highlighting the clinical challenges these conditions present to physicians.Table 1: CONTOR baseline characteristics (N=2,052)*Table 2: CONTOR baseline characteristics (N=2,052)*