Chronic Idiopathic Constipation Patients Research Articles

S523 A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy, Safety and Tolerability of ANJ908, a Novel DGAT1 Inhibitor, in Patients With Chronic Idiopathic Constipation

Introduction: Current treatment for chronic idiopathic constipation (CIC) is limited by: 1. Low magnitude of drug effect (increase of only ∼1-1.5 SBM per week) 2. Low overall response rate (typically < 20%) 3. Loss of efficacy within 3-6 months. Real-world experience where CIC patients often cycle through 2-4 pharmacotherapies shows the need for new medications with better efficacy. ANJ908 is a safe and well-tolerated diacylglycerol acyltransferase (DGAT) 1 inhibitor which increases bowel movement number and softens the stool in humans. We designed and conducted a phase 2 study of ANJ908 in CIC patients and present the data here for the first time. Methods: ANJ908C2102 was a multicenter, randomized, placebo-controlled, double-blind study designed to assess the efficacy and safety of ANJ908 in CIC patients. Patients meeting ROME IV diagnostic criteria for functional constipation (a.k.a. CIC) and had < 3 SBMs/week for prior the two weeks were eligible. Enrolled patients underwent a 2 week run-in period where all previous constipation treatment was stopped. After run-in, patients were randomized (1:1:1) to 4 weeks of once daily treatment with placebo, ANJ908 at 20 or 40 mg. Bowel movement timing, stool details, and patient reported constipation symptoms were recorded in an eDiary. Patient safety labs and AEs were monitored throughout the study. Results: A total of 191 patients were randomized. Patients were 77.9% female, with a mean (SD) age and BMI of 42.2 (14.4) years and 23.2 (4.36) kg/m2, respectively. ANJ908 increased the mean (SE) placebo-subtracted number of SBM/week by +2.28 (0.75; p = 0.0027) and +3.10 (0.74; p < 0.0001) and CSBM/week by +1.53 (0.70; p = 0.03) and +1.81 (0.70; p = 0.01), respectively at week 4. ANJ908 improved stool consistency, provided constipation relief, decreased straining severity, and reduced rescue medication use. ANJ908 was safe and generally well tolerated. Mild diarrhea, nausea and vomiting were the most common AEs with a total of 7 (out of 64) patients in the ANJ908 20 mg group discontinuing treatment due to AEs. Conclusion: ANJ908 demonstrated increases in weekly SBMs and CSBMs to a magnitude greater than previous treatments. Furthermore, ANJ908 improved patient reported stool consistency and relief of constipation symptoms. The benefit-risk profile of ANJ908 justifies advancement into phase 3 clinical development to confirm its efficacy and safety. If this profile is confirmed, ANJ908 may become a treatment better able to address the unmet need in CIC patients.

S545 Impact of Abdominal Symptoms in Patients With Chronic Idiopathic Constipation (CIC) in the United States

Introduction: Patients with CIC report a variety of abdominal symptoms beyond reduced stool frequency or straining. However, our understanding of these additional symptoms is limited. This study examined the impact of abdominal symptoms on patients with CIC. Methods: A cross-sectional, on-line health survey collected data from 8/2020-12/2021 on US adults. CIC patients were defined using Rome IV criteria. Endpoints assessed were care, symptom burden and satisfaction with control, health care provider (HCP) management and treatment of abdominal symptoms. Categorical data were described by percentage; continuous data were described by means and standard deviation. Results: Of 29,359 total participants, 9.2% (n=2,696) met criteria for CIC. CIC patients were primarily female (68.4%), White (80.9%), with a mean age of 45.1 years. Of CIC patients who sought care in the past year (58.9%), 33.1% sought care due to not getting adequate relief of and/or worsening abdominal symptoms. Of CIC patients who had an ER visit or hospitalization in the past year (15.7%) (Table), abdominal pain (84.1%), abdominal discomfort (51.2%) and abdominal bloating (42.2%) were the most common reported reasons. 91.1% of CIC patients took a medication in the past year due to abdominal pain (63.4%), abdominal discomfort (62.2%) or abdominal bloating (45.2%). Abdominal discomfort was the symptom most experienced (58.4%), while abdominal pain was the most bothersome symptom (26.5%) and the predominant symptom limiting ability to work or conduct household chores (33.6%). CIC patients were slightly more dissatisfied than satisfied with overall control of their abdominal symptoms (37.5% vs 36.1%), and more satisfied than dissatisfied with HCP management of their abdominal symptoms (49.7% vs 19.0%). Those currently taking an Rx with or without an OTC were more satisfied with the control of their abdominal symptoms than those currently taking an OTC only (50.6% vs 30.0%) (Figure). Conclusion: CIC patients suffer with abdominal symptoms typically associated with IBS-C patients highlighting the overlap of these two common disorders of gut-brain interaction. Symptom impact is high as one-third of CIC patients sought care due to abdominal symptoms, and abdominal symptoms were the most-reported reasons for ER visits or hospitalizations.Figure 1.: Satisfaction with Control, HCP Management and Treatment of Abdominal Symptoms Table 1. - Characteristics of Patients with CIC Rome IV CIC Cohort (N=2,696) % N Female 68.4% 1,843 Age, mean (SD) 45.1 (16.8) Black or African American 10.6% 286 White 80.9% 2,180 Other 8.5% 230 Proportion of Hispanic, Latino or Spanish origin 10.0% 269 Northeast 18.7% 504 Midwest 22.5% 607 South 38.2% 1,031 West 20.5% 554 Charlson Comorbidity Index (CCI) score, mean (SD) 0.8 (1.6) Body Mass Index (BMI) (lbs/in2), mean (SD) 27.8 (7.3) Median household income (Census derived from zip code), mean (SD) 64,556 (26,352) Proportion educated more than high school 75.5% 2,036 Proportion employed per Work Productivity and Impairment (WPAI) (1) 54.3% 1,111 Sought care for bowel and/or abdominal symptoms in the past 12 months 58.9% 1,589 ER visit or hospitalization for bowel and/or abdominal symptoms, past 12 months 15.7% 422 (1) Question fielded 12/20-12/21; n=2047

Chronic Idiopathic Constipation in Adults: A Review on Current Guidelines and Emerging Treatment Options.

Chronic idiopathic constipation (CIC) is a common functional bowel disorder characterized by difficult, infrequent, and/or incomplete defecation. It has a great impact on the quality of life and on health care system and represents a heavy economic burden. The diagnosis is based on symptoms, classified by the Rome IV criteria. The aim of this review was to evaluate the current therapeutic guidelines for adult CIC and highlight new emerging treatments. In detail, European, French, Spanish and Korean guidelines have been identified and compared. Osmotic laxatives, and in particular polyethylene glycol, represent the first-line therapeutic approach. Stimulant laxatives are recommended as a second-line therapy. Pelvic floor rehabilitation is recommended in patients with ano-rectal dyssynergia. In patients who fail to improve with pharmacological therapies sacral nerve stimulation is considered as last chance before surgery. Surgical approach has however limited indications in selected cases. Inertia coli refractory to any approach and obstructed defecation are two subtypes which can benefit from surgery. Among emerging agents, prucalopride, a prokinetic agent, is recommended as a second-line treatment in refractory CIC patients. In addition, the secretagogues linaclotide and plecanatide and the bile acid transported inhibitor elobixibat can be effective in patients not responsive to a second-line therapeutic regimen, although they are not worldwide commercially available.

Systematic review with meta-analysis: lubiprostone efficacy on the treatment of patients with constipation

Lubiprostone is a type 2 chloride channel activator that has been shown to be efficacious and safe in the treatment for chronic constipation. To systematically review randomized clinical trials (RCTs) assessing efficacy of lubiprostone for patients with chronic idiopathic constipation (CIC), irritable bowel syndrome with predominant constipation (IBS-C) and opioid-induced constipation (OIC). Searches were conducted in PubMed, LILACS, Cochrane Collaboration Database, and Centre for Reviews and Dissemination. Lubiprostone RCTs reporting outcomes of spontaneous bowel movements (SBM) and abdominal pain or discomfort were deemed eligible. Meta-analysis was performed calculating risk ratios and 95% confidence intervals, using the Mantel-Haenszel method and random effects model. Searches yielded 109 records representing 93 non-duplicate publications, and 11 RCTs (978 CIC, 1,366 IBS-C, 1,300 OIC, total = 3,644) met inclusion criteria. Qualitative synthesis showed that for CIC patients, lubiprostone is superior to placebo in terms of SBM outcomes. Meta-analysis for CIC was feasible for full responder and SBM within 24h rates, indicating superiority of lubiprostone over placebo. For IBS-C, lubiprostone was significantly superior for all SBM outcomes in follow-ups ranging from 1 week-3 months. In terms of abdominal pain, lubiprostone provided significantly better symptoms relief, particularly after 1 month of treatment. For OIC, lubiprostone was more effective than placebo for both SBM and discomfort measures. Our findings demonstrated that lubiprostone is superior to placebo in terms of SBM frequency for CIC, IBS-C and OIC. In terms of abdominal symptoms, the most pronounced effect was seen for abdominal pain in IBS-C patients.

S0457 Six-Month Efficacy of Polyethylene Glycol (PEG) 3350 in the Treatment of Chronic Idiopathic Constipation: Analysis Using FDA Endpoints

INTRODUCTION: PEG 3350 is an osmotic laxative approved by the FDA for the treatment of constipation in 1999 and available OTC since 2006. Studies establishing the efficacy of PEG 3350 were performed prior to the establishment of standard constipation efficacy endpoints. This post-hoc analysis re-evaluates data from a previously published trial (DiPalma J, et al. Am J Gastroenterol 2007;102:1436-1441; NCT00153153) using the FDA weekly responder definition for chronic idiopathic constipation (CIC). The overall response was analyzed using multiple intervals across 6 months. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy of PEG 3350 vs placebo in patients with CIC (modified ROME criteria). Adults with CIC were randomized (2:1) to receive PEG 3350 17g or placebo once daily for 6 months (24 weeks). This new analysis assesses the FDA CIC endpoint, defined as a weekly CSBM response (i.e., ≥3 complete spontaneous bowel movements (CSBMs) per week and an increase of ≥1 CSBM from baseline) during at least 9 of 12 treatment weeks, including 3 of the last 4 weeks of this period. Similar criteria were used to assess weekly CSBM response for the full duration of the study using an 18/24-week endpoint. Additionally, less stringent weekly CSBM response rate was analyzed using 6/12- and 12/24-week endpoints. All analyses were also completed for weekly spontaneous bowel movement (SBM) response. RESULTS: The intention-to-treat population included 204 PEG 3350–treated and 100 placebo-treated patients. At baseline, mean CSBMs (<1/wk) and mean SBMs (≤4/wk) rates were similar in both treatment arms. Weekly CSBM response for 9/12 weeks (FDA CIC endpoint) was significantly higher in the PEG 3350 group vs placebo (42% vs 13%; P < 0.0001) (Table 1). Response remained consistent for the 18/24-week CSBM analysis (43% vs 11%; P < 0.0001). Similar results were seen across the 9/12-week and 18/24-week SBM endpoints. Response rates for the 6/12-week and 12/24-week endpoints were higher for both CSBM and SBM showing overall consistency in the clinical benefits of PEG 3350 for CIC patients (P < 0.0001; Figure 1). CONCLUSION Using current definitions of treatment response based on the FDA CIC CSBM endpoint and improvements in SBM, once-daily PEG 3350 demonstrated substantial and sustained efficacy in patients with CIC over a period of 6 months.Figure 1.: CSBM and SBM response rates using different time intervalsTable 1.: CSBM and SBM outcomes

Effects of the vibrating capsule on colonic circadian rhythm and bowel symptoms in chronic idiopathic constipation.

BackgroundConstipated patients remain dissatisfied with current treatments suggesting a need for alternative therapies.AimEvaluate the mechanistic effects of oral vibrating capsule in chronic idiopathic constipation (CIC) by examining the temporal relationships between the onset of vibrations, complete spontaneous bowel movements (CSBM), and circadian rhythm.MethodsIn post hoc analyses of two double‐blind studies, CIC patients (Rome III) were randomized to receive 5 active or sham capsules/week for 8 weeks. The capsules were programmed for single vibration (study 1) or two vibration sessions with two modes, 8 hours apart (study 2). Daily electronic diaries assessed stool habit and percentage of CSBMs associated with vibrations. Responders were patients with ≥ 1 CSBM per week over baseline.Results250 patients were enrolled (active = 133, sham = 117). During and within 3 hours of vibration, there were significantly more % CSBMs in the active vs. sham group (50% vs. 42%; P = .0018). In study 2, there were two CSBM peaks associated with vibration sessions. Significantly more % CSBMs occurred in active mode 1 (21.5%) vs. sham (11.5%); (P = .0357). Responder rates did not differ in study 1 (active vs. sham: 26.9% vs. 35.9%, P = .19) or study 2 (mode 1 vs. sham: 50% vs. 31.8%, P = .24; mode 2 vs. sham: 38.1% vs. 31.8%, P = .75). Device was well‐tolerated barring mild vibration sensation.ConclusionsVibrating capsule may increase CSBMs possibly by enhancing the physiologic effects of waking and meals, and augmenting circadian rhythm, although responder rate was not different from sham. Two vibration sessions were associated with more CSBMs.

Acid Suppression Therapy Does Not Affect the Efficacy of Plecanatide: A Patient-Level Pooled Analysis of Two Large Randomized Controlled Trials

Introduction: Chronic Idiopathic Constipation (CIC) affects approximately 14% of the North American population. The most recently FDA-approved medication for the treatment of CIC is plecanatide, which is an analog of the endogenous GI peptide, uroguanylin. Like uroguanylin, it exhibits pH-sensitive activity and is most active in a slightly acidic environment. As many CIC patients may also be on concomitant acid suppressing medications such as proton pump inhibitors (PPIs) and histamine receptor antagonists (H2 blockers), it is important to determine whether plecanatide is efficacious if given with a concomitant acid suppressor. Methods: The efficacy and safety of plecanatide for the treatment of CIC has been established in two 12-week, double-blind, placebo-controlled trials. Enrolled patients met modified Rome III criteria for CIC. Patients were randomized 1:1 to plecanatide 3 mg or placebo (PBO). These phase 3 CIC studies permitted patients to enter the studies while on concomitant PPIs and/or H2 blockers if the dosing of the medication was not stopped or changed during the study. By combining data from the two phase 3 studies, there was a sufficiently large sample size to determine the efficacy of CIC patients being treated with plecanatide while on a concomitant acid suppressor. The primary endpoint for efficacy was the Efficacy Responder Rate, defined as a patient who had at least 3 complete spontaneous bowel movements (CSBMs) in a given week and an increase of at least 1 CSBM from baseline in the same week for at least 9 of the 12 treatment weeks and at least 3 of the last 4 weeks of the study. A post-hoc analysis was performed exploring the impact of concomitant acid suppressor use on efficacy parameters. Results: A total of 883 patients received plecanatide 3 mg across the two studies and 892 received PBO. Of these, approximately 10% also received concomitant treatment with acid suppressors (n=106 in the plecanatide group [96 on a PPI]; n=119 in the PBO group [102 on a PPI]). Significantly more patients who received plecanatide were Efficacy Responders as compared to PBO (23.6% plecanatide; 7.6% PBO [P=0.001]). Secondary endpoints were also significantly improved in the plecanatide group as compared to placebo (Table). Conclusion: In this subset analysis of two phase 3 trials, CIC patients treated with plecanatide, who were receiving a concomitant acid suppressing medication, demonstrated significant improvement in their constipation symptoms.444 Figure 1. Secondary Endpoint Outcome Measures

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.

Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation.

Chronic constipation affects millions of Americans, consumes significant healthcare resources, and significantly affects quality of life (QOL). Recently, several new treatment options have become available for the treatment of constipation, including intestinal secretagogues such as lubiprotone, and linaclotide, prokinetics such as prucalopride, and bile acid transporter antagonists. Plecanatide is the newest of the secretagogue class of compounds that has been approved by the US Food and Drug Administration for the treatment of adults with chronic idiopathic constipation (CIC) in the USA. It is a guanylate cyclase agonist, and a 16 amino acid synthetic peptide that is a structural analog of human uroguanylin. Two large randomized, double-blind, placebo-controlled studies assessed the efficacy and safety of plecanatide in CIC patients (Rome III). Both doses of plecanatide, 3 mg and 6 mg resulted in a significantly greater percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders (primary endpoint) compared with those who received placebo (plecanatide 3 mg, 21.0%; plecanatide 6 mg, 19.5%; placebo, 10.2%; p < 0.001 for each drug dose versus placebo). Plecanatide treatment also significantly reduced the severity of other CIC symptoms (straining effort, stool consistency, bloating). Also, plecanatide-treated patients reported high levels of satisfaction and improved QOL and desire to continue treatment. The rate of treatment-emergent adverse events with plecanatide was low, including rates of diarrhea (5%). Plecanatide is a luminally acting secretagogue that is efficacious and safe for the treatment of CIC. This article provides an overview of plecanatide in the management of adults with CIC.

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.

Treatment Algorithm for Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome Derived from a Canadian National Survey and Needs Assessment on Choices of Therapeutic Agents.

Background. Chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) are common functional lower gastrointestinal disorders that impair patients' quality of life. In a national survey, we aimed to evaluate (1) Canadian physician practice patterns in the utilization of therapeutic agents listed in the new ACG and AGA guidelines; (2) physicians satisfaction with these agents for their CIC and IBS-C patients; and (3) the usefulness of these new guidelines in their clinical practice. Methods. A 9-item questionnaire was sent to 350 Canadian specialists to evaluate their clinical practice for the management of CIC and IBS-C. Results. The response rate to the survey was 16% (n = 55). Almost all (96%) respondents followed a standard, stepwise approach for management while they believed that only 24% of referring physicians followed the same approach. Respondents found guanylyl cyclase C (GCC) agonist most satisfying when treating their patients. Among the 69% of respondents who were aware of published guidelines, only 50% found them helpful in prioritizing treatment choices and 69% of respondents indicated that a treatment algorithm, applicable to Canadian practice, would be valuable. Conclusion. Based on this needs assessment, a treatment algorithm was developed to provide clinical guidance in the management of IBS-C and CIC in Canada.

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)*

Patientsʼ Use of and Experience With Medications for Management of Symptoms of Chronic Constipation

Introduction: Chronic idiopathic constipation (CIC) patients experience both, bowel and abdominal symptoms. Patients often manage symptoms through use of over-the-counter laxatives, stool softeners, as well as prescription medications. However, little is known regarding patient experience with these treatments. The objective of this study was to evaluate CIC patients' experience with treatments used for management of CIC symptoms. Methods: At screening for a Phase 3b, double-blind, randomized, controlled trial, patients meeting modified Rome II criteria for CIC and prominent abdominal bloating (≥5 on 11-pt numerical rating scale) completed a questionnaire regarding prior medication use [polyethylene glycol (PEG), psyllium (P), wheat dextrin (WD), stimulant laxative (SL), docusate (DS), or lubiprostone (Lubi)] during the prior 6 months. Questions assessed frequency and duration of use; confidence (3-pt scale) in having ≥1 bowel movement (BM) every other day while taking medication; predictability of BM timing (3-pt scale); and treatment satisfaction (5-pt scale) for relief of constipation symptoms, abdominal discomfort, and abdominal bloating. Results: Of 1423 screened patients who completed the survey, 1009 (71%) reported taking ≥1 constipation medication in the prior 6 months. Duration of single medication use ≥ 1 month ranged from 53% (WD) to 76% (SL). The percentage of patients not at all confident in having at least one BM every other day while taking the medication ranged from 30% (SL) to 64% (WD).The percentage of patients who reported unpredictable BM timing after taking medication ranged from 51% (SL) to 81% (WD). The percentage of patients who were not at all or a little satisfied with the medications' ability to: (1) relieve constipation symptoms ranged from 48% (SL) to 83% (WD), (2) relieve abdominal discomfort ranged from 59% (SL) to 81% (WD), and (3) relieve abdominal bloating ranged from 69% (SL) to 90% (BL) (Table). Conclusion: Overall, the majority of CIC patients were not at all or a little satisfied with prior medications' ability to relieve constipation and abdominal symptoms of discomfort and bloating. Approximately one half to two thirds of patients lacked confidence for having a BM at least once every other day, and for the majority, timing of their BMs was not predictable. Unmet need for management of CIC symptoms continues to exist with older, commonly used treatments.Table 1

Patient Attitudes Regarding Treatment Satisfaction and Bowel Movement Confidence and Predictability: A Post-hoc Comparison of Study Treatment and Prior Medication Use Based on a Phase 3b Trial of Linaclotide in CIC

Introduction: Linaclotide (LIN) is approved in the US for adult treatment of chronic idiopathic constipation (CIC). CIC patients experience multiple bowel (infrequent bowel movements, hard/lumpy stools, straining) and abdominal (discomfort & bloating) symptoms. This analysis compared CIC patient attitudes regarding the study drug and prior constipation medications (PCMs) from a Phase 3b trial. Methods: A Phase 3b randomized, double-blind, placebo-controlled trial of LIN (145 or 290 μg) was conducted among CIC patients with prominent abdominal bloating at baseline. At screening, patients identified constipation medications used in the prior 6 months (bulk laxatives [BL], lubiprostone [LUBI]) polyethylene glycol [PEG], stimulant laxatives [SL], stool softeners [SS], wheat dextrin [WD]) and reported their confidence in having ≥1 bowel movement (BM) every other day and their ability to predict timing of BMs after medication use, each on a 3-pt scale, and satisfaction with the medication's ability to relieve constipation symptoms on a 5-pt scale. Patient responses were analyzed by study drug and PCMs by comparing 12 week on-study averages and one-time screening responses using age-adjusted means. Results: Overall, 153 patients were treated with LIN 145, 159 with LIN 290, and 171 with placebo. Patients reporting each type of PCM numbered from 13 (WD) to 91 (SL). LIN 145-treated patients were statistically significantly (α = 0.05) more confident in having ≥1 BM every other day compared with those who reported using BL, SS, & WD prior to study start; LIN 290-treated patients were significantly more confident than those who reported use of BL & WD (Fig 1). Predictability of timing of BM after medication use was significantly better for LIN 145 compared with BL, LUBI, SL, SS, & WD and for LIN 290 compared with BL, PEG, SS, & WD (Fig 2). Satisfaction was significantly higher for LIN 145 compared with BL, SL, SS, & WD and for LIN 290 compared with BL, PEG, SS, & WD (Fig 3).Figure 1Figure 2Figure 3Conclusion: Although the trial was not powered for this analysis, patients reported LIN as being significantly better than 2-3 PCMs in confidence of having ≥1 BM every other day and better than 4-5 PCMs in predictability of BM timing after medication use. Patients reported significantly higher satisfaction in the ability of LIN to relieve constipation symptoms in comparison to 4 PCMs.

Sustainability of Linaclotide Response in Chronic Idiopathic Constipation Patients: A Post-hoc Pooled Analysis of Two Phase 3 Trials

Introduction: Linaclotide (LIN), a guanylate cyclase-C agonist, is approved in the US at a dose of 145 μg for treatment of chronic idiopathic constipation (CIC) in adults. Approval was based on two phase 3, randomized, placebo-controlled trials; the primary efficacy endpoint was met in each. Clinicians and regulatory agencies are increasingly interested in sustainability of CIC treatment response. The aims of this post-hoc analysis were to assess sustained response to LIN and examine differences between sustained responders and primary-efficacy (12-week) responders in the phase 3 trials. Methods: CIC patients were randomized 1:1:1 to receive placebo (PBO), or LIN 145 μg or 290 μg once daily for 12 weeks. Patient populations were pooled across the two nearly identical trials by treatment. Weekly response was defined as ≥3 complete, spontaneous bowel movements (CSBMs)/week and an increase from baseline of ≥1 CSBM/week; patients without CSBM data (missing or discontinued before that week) were considered weekly nonresponders. Both the 12-week and the sustained responder definitions required weekly response for ≥9 of 12 weeks. In addition, sustained responders must have had a weekly response for ≥3 of the last 4 treatment weeks. 12-week responder and sustained responder rates were evaluated; frequency of weekly response in the last 4 of 12 weeks was analyzed by the frequency of weekly response in the first 8 weeks. Sustained responder rates were also analyzed in the individual trials. Results: The pooled analysis included 423 PBO, 430 LIN 145 μg, and 418 LIN 290 μg patients; 4.7% of PBO patients were 12-week responders compared to 18.6% of LIN 145 μg patients (p < 0.0001) and 20.3% of LIN 290 μg patients (p < 0.0001). Sustained responder rates were 4.3% of PBO patients compared to 16.3% of LIN 145 μg patients (p < 0.0001) and 18.7% of LIN 290 μg patients (p < 0.0001); differences versus PBO were significant in each trial (Table 1). Of the 12-week responders who were not sustained responders, the majority had a weekly response for 2 of the last 4 weeks (Table 2).Table 1: Responder Rates: 12-Week Responders and Sustained RespondersTable 2: Frequency of Weekly Response in the Last 4 of 12 Treatment Weeks by Frequency in the First 8 Weeks Pooled PopulationConclusion: In this post-hoc pooled analysis of two 12-week phase 3 CIC trials, significantly more LIN patients than PBO patients showed sustained response in CSBM frequency. The efficacy results demonstrated by sustained responders are similar to those demonstrated by the 12-week primary efficacy responder endpoint; in that 87.5% of LIN 145 μg and 91.8% of LIN 290 μg patients meeting the 12-week responder definition were also sustained responders.

A National Survey and Needs Assessment on Choices of Therapeutic Agents for Chronic Idiopathic Constipation and Constipation Predominant Irritable Bowel Syndrome: A Canadian Perspective

Introduction: Chronic Idiopathic Constipation (CIC) and constipation-predominant Irritable Bowel Syndrome (IBS-C) are common functional lower gastrointestinal disorders that impair patients' quality of life; despite this, therapies remain unsatisfactory to patients and treating physicians. In 2014, ACG and AGA published two clinical guidelines independently. In a national survey, we aim to evaluate: 1. Canadian gastroenterologists (GIs) practice patterns in the utilization of therapeutic agents listed in the two guidelines; 2. GIs satisfaction with these agents for their CIC and IBS-C patients; and 3. the usefulness of these new guidelines in their clinical practice. Methods: In February 2015, a 9-item questionnaire was sent to 350 Canadian GIs (Converge, Toronto, ON, Canada) to determine their practice demographic information and practice approaches to CIC and IBS-C management including stool softener, fibre supplement, stimulant and osmotic laxative, 5-HT4 agonist and guanylate cyclase-C (GCC) agonist therapies. The study closed in May 2015. Results: The response rate to the survey was 15% (n=52). Almost all (96%) responders follow a standard, stepwise approach for managing patients with CIC and IBS-C. However, they believe that only 23% of referring physicians follow the same approach. Reported first-line therapy (osmotic laxatives) was similar for IBS-C and CIC but second-line therapy differed for CIC (bulking agents) and IBS-C (GCC agonist). Nearly 80% of responders indicated that GCC agonists were the most satisfactory therapy for IBS-C and CIC; despite this, 61% of responders and 64% of referring physicians (reported by the responders) are reluctant to move from over-the-counter to prescription agents. Among the 68% of responders who are aware of the 2 published guidelines, only 51% found the guidelines helpful in prioritizing treatment choices, and 69% of responders indicated that a treatment algorithm, applicable to Canadian practice, would be valuable. Conclusion: This survey demonstrates a need for an education program to standardize and enhance the treatment of CIC and IBS-C. The majority of Canadian GIs would welcome a practical management algorithm to translate new published guidelines and the role of new therapeutic agents into clinical practice. Based on this needs assessment, a comprehensive treatment algorithm has been developed and will be evaluated for the management of IBS-C and CIC in Canadian practice.

Treatment Expectations and Drivers of Treatment Satisfaction Among Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome With Constipation (IBS-C) Patients

Introduction: To better understand, through qualitative research, treatment expectations and drivers of treatment satisfaction among patients with chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Methods: Semistructured, qualitative interviews were conducted with 40 adult patients in the United States (21 CIC, 19 IBS-C) following participation in a long-term safety study, which involved taking study treatment for CIC/IBS-C. Patients were asked to describe factors that influenced their treatment expectations, satisfaction with the study treatment, and the characteristics of an ideal CIC/IBS-C treatment. Qualitative analysis of verbatim transcripts was performed using ATLAS.ti software and thematic analysis methods. Following the interview, patients completed a survey in which they rated the treatment attributes they considered most important and the symptoms they most wanted to see improve with treatment. Results: The majority of CIC (86%) and IBS-C (74%) patients were satisfied with the study treatment. Primary drivers of treatment satisfaction for both CIC and IBS-C patients included passing bowel movements (BMs) daily, predictability of BM timing, and resolution of abdominal symptoms. Across both conditions, the symptoms patients reported as most important for an ideal treatment to treat included BM frequency (with the aim of achieving BMs that were frequent/daily and predictable in timing), abdominal pain/discomfort, and abdominal bloating. Some differences by condition were noted in patients’ descriptions of an ideal treatment. For example, a higher proportion of IBS-C patients (89%) highlighted desiring predictable BMs, compared with CIC patients (52%). Similarly, a larger proportion of IBS-C patients considered abdominal pain important to improve (IBS-C=68%; CIC=43%). The majority of CIC patients (62%) identified achieving a normal stool consistency as an ideal treatment characteristic, compared with only 11% of IBS-C patients. The treatment attributes patients rated most highly were low cost, daily administration, oral, solid formulation, effective in relieving symptoms, and no side effects apart from diarrhea. Conclusion: The findings provide evidence regarding drivers of treatment satisfaction and important attributes of an ideal treatment for CIC and IBS-C from the patient perspective. Generally, patients desire a treatment that improves both bowel and abdominal symptoms of CIC and IBS-C at a reasonable cost and is easy to take. As treatment satisfaction is an important driver of treatment adherence, it is critical that the above factors are considered when developing new CIC and IBS-C treatments. Disclosure - Rob Arbuckle is an employee of Adelphi Values, Ltd, which is a consultancy whose activities related to the project are funded by Forest Research Institute, and Ironwood Pharmaceuticals; Brooke. Witherspoon is a consultant to Ironwood Pharmaceuticals, Inc and Forest Research Institute; Robyn Carson is an employee of Forest Research Institute and owns stock and/or stock options in Forest. Laboratories, Inc. This research was supported by an industry grant from Forest Research Institute and Ironwood Pharmaceuticals.