Irritable Bowel Syndrome With Constipation Symptoms Research Articles

Plecanatide Improves Symptoms of Irritable Bowel Syndrome with Constipation: Results of an Integrated Efficacy and Safety Analysis of Two Phase 3 Trials.

Patients with irritable bowel syndrome with constipation (IBS-C) experience abdominal pain with altered bowel movements. Plecanatide is indicated as IBS-C treatment in adults. This integrated analysis further characterizes plecanatide efficacy and safety in IBS-C. Data pooled from 2 identically designed phase 3 trials included adults with IBS-C randomized to plecanatide 3 mg or 6 mg, or placebo once daily for 12 weeks. A daily diary recorded stool frequency/symptoms, with abdominal pain, bloating, cramping, discomfort, fullness, and straining intensity individually rated. Overall response (primary endpoint) was defined as ≥30% improvement from baseline in average worst abdominal pain severity and increase of ≥1 complete spontaneous bowel movement, during same week (composite), for ≥6 of 12 weeks. Secondary endpoints included sustained response (overall response, plus meeting weekly composite criteria during ≥2 of last 4 treatment weeks) and changes from baseline in individual symptoms. Safety assessments included adverse event monitoring. Overall, 2176 patients (74.0% female; mean [SD] age, 43.5 [14.1] years) were included in efficacy analyses (plecanatide 3 mg [n = 724], 6 mg [n = 723], placebo [n = 729]). A significantly greater percentage of patients achieved overall response with plecanatide 3 mg (25.6%) and 6 mg (26.7%) versus placebo (16.0%; both P < 0.001 vs placebo). A significantly greater percentage of patients were sustained responders with plecanatide 3 mg (24.3%) and 6 mg (25.6%) versus placebo (15.6%; both P < 0.001 vs placebo). Significant improvements from baseline in abdominal discomfort, abdominal fullness, abdominal pain, bloating, and cramping occurred as early as Week 1 (Week 2 for abdominal pain) with plecanatide and were maintained through Week 12 versus placebo. Diarrhea, the most common adverse event, occurred in 4.3% (3 mg), 4.0% (6 mg) and 1.0% (placebo) of patients, leading to study discontinuation in 1.2%, 1.4%, and 0 patients, respectively. Plecanatide is safe and effective for treating global and individual IBS-C symptoms.

Burden of Constipation: Looking Beyond Bowel Movements.

Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) are associated with significant social and economic burdens. To address these burdens, a deeper understanding of their root causes is required. A discrepancy exists between patients' and healthcare providers' (HCPs) perceptions of constipation symptoms and the impact of symptoms associated with CIC and IBS-C. Compared with the HCPs' perceptions of patients' symptoms, a greater percentage of patients report acceptance and feeling in control of their CIC or IBS-C symptoms. Unfortunately, only one-third of individuals with CIC or IBS-C formally consult an HCP about their constipation. Fewer than half take medications, and these are generally over-the-counter therapies rather than prescription therapies. For those who seek help, only one-fifth feel that their constipation symptoms are well managed. Notable sex and cultural differences exist regarding individuals consulting their HCP about constipation. Many individuals with CIC and IBS-C remain inadequately managed and unduly affected, contributing to the high social and economic burden of these conditions.

Tegaserod for Irritable Bowel Syndrome With Constipation in Women Younger Than 65 Years Without Cardiovascular Disease: Pooled Analyses of 4 Controlled Trials.

INTRODUCTION:Tegaserod was the first US Food and Drug Administration–approved drug for irritable bowel syndrome with constipation (IBS-C) in women and was recently reapproved for use. Recognizing that clinical trials were performed almost 20 years ago, we performed an integrated analysis on patient-reported outcomes relevant to current practice including previously unpublished data.METHODS:Data from 4 12-week, randomized, placebo-controlled trials evaluating tegaserod 6 mg b.i.d. in patients with IBS-C were pooled. We analyzed 2 groups: all women (overall population) and women younger than 65 years without a history of cardiovascular ischemic events (indicated population). The primary end point was subjective global assessment of IBS-C symptom relief. Responders rated themselves as “considerably” or “completely” relieved ≥50% of the time or at least “somewhat relieved” 100% of the time over the last 4 weeks.RESULTS:The overall and indicated populations included 2,939 (tegaserod [n = 1,478]; placebo [n = 1,461]) and 2,752 (tegaserod [n = 1,386]; placebo [n = 1,366]) participants, respectively. The pooled odds ratios (95% confidence interval) for clinical response during the last 4 weeks in the overall and indicated populations with tegaserod were 1.37 (1.18, 1.59; P < 0.001) and 1.38 (1.18, 1.61; P < 0.001). In the overall and indicated populations, clinical response rates for tegaserod during the last 4 weeks were 43.3% and 44.1% versus 35.9% and 36.5% with placebo (P < 0.001). Adverse events were similar between groups. No significant cardiovascular events related to tegaserod were observed in patients with ≤1 cardiac risk factor.DISCUSSION:Tegaserod 6 mg b.i.d. reduced IBS-C symptoms in overall and US Food and Drug Administration–indicated populations (women aged <65 years with no history of cardiovascular ischemic events).

Efficacy and Safety of 5-HT4 Receptor Agonist Minesapride for Irritable Bowel Syndrome with Constipation in a Randomized Controlled Trial

Treatment options for irritable bowel syndrome with constipation (IBS-C) are limited-new prokinetic drugs are needed. We evaluated the efficacy and safety of minesapride (DSP-6952), a partial agonist with high affinity for 5-HT4 receptors, in patients with IBS-C in Japan. We performed a double-blind phase 2 study of 171 patients with Rome III-defined IBS-C at 33 centers in Japan, from December 2012 through August 2013. Patients were randomly assigned to groups given minesapride (1, 4, 12, or 40 mg) or placebo once daily for 4 weeks. The primary outcome was efficacy, defined as improvement in the weekly frequency of complete spontaneous bowel movements (CSBMs), abdominal symptoms, and IBS-C symptoms (according to the Japanese version of the IBS severity index score). For evaluation of safety, adverse events (AEs) were recorded. The least squares mean change from baseline in the weekly frequency of CSBMs was greater in all minesapride groups than in the placebo group at week 4 (40 mg vs placebo, P = .040). The abdominal symptoms score improved in minesapride 40 mg group. The overall IBS severity index score decreased from baseline to week 4 in all treatment groups-especially in the 12 mg and 40 mg groups (P = .048 and <.001 vs placebo, respectively). The proportions of patients with treatment-emergent AEs in the pooled minesapride and placebo groups were 55.0% and 60.0%, respectively. The most common treatment-emergent AE was diarrhea (in 42.9% and 37.1% of patients in the pooled minesapride and placebo groups, respectively). In a phase 2 trial of patients with IBS-C in Japan, minesapride increased stool frequency (measured by CSBMs), reduced abdominal and overall IBS-C symptoms, and was well tolerated. Japan Pharmaceutical Information Center trial no: JapicCTI-122041.

A retrospective and prospective 12-month observational study of the socioeconomic burden of moderate to severe irritable bowel syndrome with constipation in Spain

IntroductionThe socioeconomic burden of irritable bowel syndrome with constipation (IBS-C) has never been formally assessed in Spain. Patients and methodsThis 12-month (6-month retrospective and prospective periods) observational, multicentre study assessed the burden of moderate-to-severe IBS-C in Spain. Patients were included if they had been diagnosed with IBS-C (Rome III criteria) within the last 5 years and had moderate-to-severe IBS-C (IBS Symptom Severity Scale score [IBS-SSS] ≥175) at inclusion. The primary objective was to assess the direct cost to the Spanish healthcare system (HS). ResultsA total of 112 patients were included, 64 (57%) of which had severe IBS-C at inclusion. At baseline, 89 (80%) patients reported abdominal pain and distention. Patient quality of life (QoL), measured by the IBS-C QoL and EQ-5D instruments, was found to be impaired with a mean score of 59 and 57 (0–100, worst-best), respectively. Over the 6-month prospective period the mean IBS-C severity, measured using the IBS-SSS showed some improvement (315–234 [0–500, best–worst]). During the year, 89 (80%) patients used prescription drugs for IBS-C, with laxatives being the most frequently prescribed (n=70; 63%). The direct cost to the HS was €1067, and to the patient was €568 per year. The total direct cost for moderate-to-severe IBS-C was €1635. DiscussionThe majority of patients reported continuous IBS-C symptoms despite that 80% were taking medication to treat their IBS-C. Overall healthcare resource use and direct costs were asymmetric, with a small group of patients consuming the majority of resources.

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.

Clinical response to linaclotide at week 4 predicts sustained response in irritable bowel syndrome with constipation and improvements in digestive and extra-digestive symptoms.

Background:Linaclotide is approved for the treatment of moderate-to-severe irritable bowel syndrome (IBS) with constipation (IBS-C) in adults. This study aimed to assess factors predictive of a clinical response and improvements in non-IBS symptoms with linaclotide treatment in a Spanish patient population.Methods:In this open-label phase IIIb study, patients with moderate-to-severe IBS-C received linaclotide 290 μg once daily for 12 weeks. The primary endpoint was clinical response at week 12, defined as >30% reduction in IBS symptom severity score (IBS-SSS) or IBS-SSS <75 plus self-reported response of feeling ‘better’ or ‘much better’ versus the baseline. Digestive nonintestinal and extra-digestive symptom scores were assessed. Baseline characteristics and week 4 clinical response were assessed as predictors of week 12 clinical response.Results:A total of 96 patients were eligible; 91 were female and the mean age was 47.4 years. Mean (SD) baseline IBS-SSS was 371 (72.5). In the intention-to-treat and per-protocol populations, 22.9% and 31.7% were clinical responders at week 4, respectively, and 25.0% and 36.7% were clinical responders at week 12. Digestive nonintestinal and extra-digestive symptom scores were significantly improved at weeks 4 and 12. Baseline characteristic was not associated with week 12 clinical response; however, clinical response at week 4 was predictive of response at week 12 (OR: 6.5; 95%IC: 2.1–19.8). The most common adverse event was diarrhea inclusive of loose or watery stools (35.4%).Conclusions:Linaclotide improves IBS-C symptoms, including digestive nonintestinal and extra-digestive symptoms. A clinical response at week 4 may predict response at week 12.

Impact of symptoms by gender and age in Japanese subjects with irritable bowel syndrome with constipation (IBS-C): a large population-based internet survey

BackgroundIrritable bowel syndrome with constipation (IBS-C) is a representative psychosomatic disorder. Several pathophysiological factors have been linked to IBS symptoms such as the modulation of gastrointestinal motility, visceral hypersensitivity, dysregulation of the gut-brain axis, genetic and environmental factors, sequelae of infection, and psychosocial disorders. It is likely that biopsychosocial aspects of IBS-C underlie its gender and age effects. However, the influence of each symptom of IBS-C by gender and age is not well understood. We hypothesized that the expression rate of each IBS-C symptom in females and in subjects aged 20–49 years was higher than that of subjects who were male and aged 50–79 years.MethodsWe conducted an internet survey of 30,000 adults from the general Japanese population. IBS-C subjects were asked to answer a questionnaire on the degree of anxiety, thoughts about bowel habits, and their dominant gastrointestinal symptoms together with exacerbation factors. The correlation between gender and age and IBS-C symptoms was analyzed.ResultsWhen analyzed by gender, the expression rate of abdominal discomfort, abdominal distention, and abdominal fullness was significantly higher in female than male IBS-C subjects (66.5% vs. 58.7%, p < 0.05; 54.7% vs. 43.6%, p < 0.01; 18.9% vs. 9.6%, p < 0.01, respectively). When analyzed by age, the expression rate of abdominal distention and abdominal pain was significantly higher among IBS-C subjects aged 20–49 years than those aged 50–79 years (55.7% vs. 46.8%, p < 0.05; 36.6% vs. 20.6%, p < 0.001, respectively). In contrast, there was no gender or age differences with regard to the most common and bothersome symptom (abdominal bloating) among IBS-C subjects.ConclusionsThe expression rate of some IBS-C symptoms was higher among females and those aged 20–49 years than males and those aged 50–79 years, respectively. It is important to understand the impact of symptoms by gender and age to evaluate the pathology of IBS-C from a biopsychosocial perspective.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).

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.

Characteristics Associated With Probiotic Use Among Patients Experiencing Constipation-Related Symptoms: Results From the CONTOR Study

Introduction: Among patients with irritable bowel syndrome with constipation (IBS-C) and chronic constipation (CC), treatment often includes over-the-counter products, such as probiotics. This analysis describes characteristics of CONTOR respondents who did and did not report probiotic use. Methods: Fully-insured patients aged ≥18 years were identified from a large, geographically-diverse US health plan from December 2012 to April 2014. Identification criteria included ≥1 medical claim with an ICD-9 diagnosis code for constipation (564.0x), IBS (564.1x) or abdominal pain (789.0x), plus ≥1 pharmacy claim for a stool softener/laxative; or ≥1 pharmacy claim for linaclotide or lubiprostone. Patients were invited by mail to participate in the study and complete a self-administered paper survey assessing symptoms, treatment, and quality of life. Respondents were included in the probiotic user analytic group if they reported probiotic use in the past 6 months.Table 1: Characteristics of Probiotic Use among CONTOR respondentsResults: Among the 9,590 patients who met the inclusion criteria and were invited to participate in the CONTOR study, 1,136 eligible patients responded and are included in this analysis. Most respondents were female (94%); mean age (SD) was 47(12) years. Overall, 610 (54%) reported probiotic use in the past 6 months; of these, 61% reported use in the past 7 days. Demographic characteristics of probiotic users were not significantly different from non-users (n=526) with the exception of race, where probiotic users were less likely to be black (p=0.004) and more likely to be Asian (p=0.017). Probiotic users were more likely to report a health care provider diagnosis of IBS-C (p < 0.001), and to report symptoms consistent with modified Rome III IBS-C criteria (p=0.002). Probiotic users reported more severe abdominal symptoms (PAC-SYM) and lower symptom-related quality of life overall and on 3 of the 4 subscales of the PAC-QOL (Table). Conclusion: Compared to non-users, probiotic users were more likely to have a diagnosis of IBS-C, severe abdominal symptoms, and lower quality of life than other respondents in the CONTOR study. Over half of study respondents reported probiotic use, highlighting the widespread use of probiotics by patients with gastrointestinal symptoms, especially IBS-C, despite inconclusive evidence on the benefit of probiotics in treating these conditions. It is unknown, based on these data, whether probiotics are used more commonly because of more severe IBS-C symptoms or if probiotics may be causing more severe symptoms.

PWE-251 Diagnosis and management of moderate-to-severe irritable bowel syndrome with constipation (IBS-C) in the UK: the IBIS-C study

Introduction The IBIS-C study assessed the burden of IBS-C in 6 European countries (France, Germany, Italy, Spain, Sweden, and UK). Here we present the diagnosis and management results for the UK. Method Observational study in patients (pts) diagnosed with moderate-to-severe IBS-C in the last five years (Rome-III criteria) with a 12-month follow-up (6 months retrospective and 6 months prospective, in order to assess health resource utilisation [HRU] prior to and after an active phase of the disease). Moderate-to-severe IBS-C was defined as an IBS-Symptom Severity Score (IBS-SSS) ≥175. Results 104 pts were included (79% severe, mean age [±SD] 45.5 ± 14.6 years old, 93% female). Mean time since diagnosis: 2.6 ± 4.0 years; mean symptom duration: 15.3 ± 14.9 yrs. Diagnostic procedures were highly variable; the most common were blood tests (72%), colonoscopy (69%), and abdominal ultrasound (55%). At inclusion the most prevalent symptoms were abdominal pain (92%) and bloating (91%). Main ongoing comorbidities were anxiety (50%), chronic pain (44%), headache (40%), insomnia (33%), or dyspepsia (31%). 52% of pts had an average of 3.6 ± 2.7 diagnostic tests during follow-up, the most common were haematology (29%) and clinical chemistry (29%) blood tests, and colonoscopy (13%). 93% of pts took prescription drugs (90% took prescription drugs for their IBS-C). The most common medication groups were: laxatives (81%), prokinetics (32%), antispasmodics (20%), and analgesics (18%) alone or in combination. Overall, 63% of pts took OTC medication for their IBS-C; the most common were laxatives (37%), prebiotics/probiotics (14%), and peppermint oil (14%). In addition, 36% of pts received complementary therapies. Overall, marginal improvement was noted in symptom severity (IBS-SSS total score) between baseline (373 ± 83) and the 6-month visit (324 ± 113). Conclusion Moderate-to-severe IBS-C symptoms often remain undiagnosed for many years and degree of control does not improve over time even though there is a high degree of prescription medication use. Consequently, moderate-to-severe IBS-C continues to be a burden despite the availability of therapeutic interventions. Disclosure of interest Y. Yiannakou Conflict with: Grants: Shire; Medtronic. Speaker fees: Almirall; Shire; Sucampo, M. Eugenicos Conflict with: Consultant/Advisory Board Member: Almirall; Astellas; Dr Falk Pharma; NAPP; and Shire., D. Sanders Consultant for: Almirall, A. Emmanuel Conflict with: Advisory Board and Educational Talk honoraria: Almirall., P. Whorwell Conflict with: Consultant/research grant support: Almirall; Chr. Hansen; Danone Research; Ironwood; Salix; Shire; Sucampo., F. Butt: None Declared, S. Bridger: None Declared, N. Arebi: None Declared, A. Millar Conflict with: The hospital received payment from Almirall for the conduct of the study, V. Kaushik Conflict with: Advisory Board and Educational Talk honoraria: Almirall. Meeting support: Cooks; Tillotts; AbbVie, M. Rance Employee of: Almirall, J. Mackinnon Employee of: TFS Develop S. L, contracted by Almirall S. A to conduct the study, J. Bertsch Employee of: TFS Develop S. L, contracted by Almirall S. A to conduct the study, J. Fortea Employee of: Almirall, J. Tack Conflict with: Grants/research support: Abbott; Novartis; Shire. Honoraria/consultancy fees: Almirall; AstraZeneca; Danone; GI Dyamics; GlaxoSmithKline; Ironwood; Janssen; Menarini; Novartis; Rhythm; Shire; Takeda; Theravance; Tsumura; Will Pharma; Zeria. Speaker fees: Abbott; Almirall; AstraZeneca; Janssen; Menarini; Novartis; Shire; Takeda; Zeria.

Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic Guanosine 3′,5′-Monophosphate

Linaclotide is a minimally absorbed agonist of guanylate cyclase-C (GUCY2C or GC-C) that reduces symptoms associated with irritable bowel syndrome with constipation (IBS-C). Little is known about the mechanism by which linaclotide reduces abdominal pain in patients with IBS-C. We determined the effects of linaclotide on colonic sensory afferents in healthy mice and those with chronic visceral hypersensitivity. We assessed pain transmission by measuring activation of dorsal horn neurons in the spinal cord in response to noxious colorectal distention. Levels of Gucy2c messenger RNA were measured in tissues from mice using quantitative reverse transcription polymerase chain reaction and in situ hybridization. We used human intestinal cell lines to measure release of cyclic guanosine-3',5'-monophosphate (cGMP) by linaclotide. We performed a post-hoc analysis of data from a phase III, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290 μg linaclotide once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain. In mice, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity. Intra-colonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide's target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors. The effects of linaclotide were lost in Gucy2c(-/-) mice and prevented by inhibiting cGMP transporters or removing the mucosa. During 26 weeks of linaclotide administration, a significantly greater percentage of patients (70%) had at least a 30% reduction in abdominal pain compared with patients given placebo (50%). We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C.

PWE-025 Assessing the Percent of Days Linaclotide Improved Abdominal Symptoms and Stool Frequency in Patients with Irritable Bowel Syndrome with Constipation (IBS-C): Pooled Analysis of 2 Phase 3 Trials

IntroductionLinaclotide (LIN), a minimally absorbed guanylate cyclase C agonist (GCCA), improved abdominal symptoms and bowel movement (BM) frequency in patients (pts) with IBS-C in 2 Phase 3 trials. This post-hoc...

Randomised clinical trials: linaclotide phase 3 studies in IBS‐C – a prespecified further analysis based on European Medicines Agency‐specified endpoints

Treatment options that improve overall symptoms of irritable bowel syndrome with constipation (IBS-C) are lacking. A prespecified further analysis to evaluate the efficacy and safety of linaclotide, a guanylate cyclase C agonist, in patients with IBS-C, based on efficacy parameters prespecified for European Medicines Agency (EMA) submission. Two randomised, double-blind, multicentre Phase 3 trials investigated once-daily linaclotide (290 μg) for 12 weeks (Trial 31) or 26 weeks (Trial 302) in patients with IBS-C. Prespecified primary endpoints were the EMA-recommended co-primary endpoints: (i) 12-week abdominal pain/discomfort responders [≥30% reduction in mean abdominal pain and/or discomfort score (11-point scales), with neither worsening from baseline, for ≥6 weeks] and (ii) 12-week IBS degree-of-relief responders (symptoms 'considerably' or 'completely' relieved for ≥6 weeks). Overall, 803 (Trial 31) and 805 patients (Trial 302) were randomised. A significantly greater proportion of linaclotide-treated vs. placebo-treated patients were 12-week abdominal pain/discomfort responders (Trial 31: 54.8% vs. 41.8%; Trial 302: 54.1% vs. 38.5%; P < 0.001) and IBS degree-of-relief responders (Trial 31: 37.0% vs. 18.5%; Trial 302: 39.4% vs. 16.6%; P < 0.0001). Similarly, significantly more linaclotide- vs. placebo-treated patients were responders for ≥13 weeks in Trial 302 (abdominal pain/discomfort: 53.6% vs. 36.0%; IBS degree-of-relief: 37.2% vs. 16.9%; P < 0.0001). The proportion of sustained responders (co-primary endpoint responders plus responders for ≥2 of the last 4 weeks of treatment) was also significantly greater with linaclotide vs. placebo in both trials (P < 0.001). Linaclotide treatment significantly improved abdominal pain/discomfort and degree-of-relief of IBS-C symptoms compared with placebo over 12 and 26 weeks. ClinicalTrials.gov (identifiers: NCT00948818 and NCT00938717).

Tu1068 Effects of Linaclotide Treatment on Patient-Reported Ratings of Change for Symptoms of Irritable Bowel Syndrome With Constipation (IBS-C): Pooled 12-Week Findings From Two Phase 3 Trials

Introduction: Linaclotide, an investigational drug, is a minimally-absorbed guanylate cyclaseC receptor agonist that has demonstrated symptom improvement in IBS-C patients in two large Phase 3 trials. Patient-reported ratings of change for individual and overall IBS-C symptoms provide interpretation of clinical relevance for patient-reported outcome measures of abdominal and bowel symptoms. Aim: To examine the effects of linaclotide on patientreported ratings of change and the extent of improvement in individual IBS-C symptoms within these patient-reported ratings of change categories. Methods: In two Phase 3 IBS-C trials of linaclotide, patients reported daily ratings for abdominal symptoms (pain, bloating, fullness, cramping, discomfort) and bowel symptoms (spontaneous bowel movement [SBM] and complete SBM [CSBM] frequency, straining, stool consistency, unsuccessful BM attempts) via an interactive voice response system diary (pooled data). Patient-reported ratings of change included relief or improvement for each specific abdominal and bowel symptom, respectively, for the prior 7 days, at study visits during weeks 2, 4, 8, and 12 of the Treatment Period, compared to before the trial began, using a 7-point balanced ordinal scale (1= completely improved/relieved, 4=unchanged, 7=as bad as I can imagine). Overall Degree of Relief of IBS symptoms was also assessed weekly using the same 7-point balanced scale. P-values were obtained from the Cochran-Mantel-Haenszel (CMH) row-mean score tests comparing linaclotide to placebo. Results: For all of the patient-reported rating-of-change parameters, significantly more linaclotide vs placebo patients were completely/considerably relieved (Table 1); additionally, more placebo than linaclotide patients reported their symptoms as unchanged, somewhat worse or considerably worse/as bad as I can imagine. Although patients on linaclotide, in general, reported greater improvement in symptoms across all categories of relief/improvement, patients who had greater relief/improvement ratings tended to report greater changes in symptom score for the corresponding symptom, regardless of treatment group assignment (Table 2). Within the category of completely/considerably relieved, patients on linaclotide tended to report greater benefit than those patients on placebo. Conclusions: In clinical studies, linaclotide was approximately twice as likely as placebo to provide complete or considerable relief for overall and individual abdominal and bowel symptoms in IBS-C patients. Nearly half of IBS-C patients randomized to linaclotide reported complete/considerable relief of their IBS symptoms. This analysis provides perspective on themagnitude of change in patients' individual symptoms that corresponds to reporting of complete/considerable relief of their individual and overall IBS-C symptoms. Table 1. Patient-Reported Rating of Change (Week 12), Percentage of Patients in Each Category by Treatment Group

Tu1402 Impact of Linaclotide Treatment on Work Productivity and Activity Impairment in Adults With Irritable Bowel Syndrome With Constipation

Background: Irritable bowel syndrome with constipation (IBS-C) is a chronic functional gastrointestinal disorder characterized by abdominal pain or discomfort with bowel symptoms of constipation. IBS-C has been shown to decrease work productivity and increase activity impairment, resulting in a substantial economic burden for patients and employers. Linaclotide is an investigational minimally absorbed guanylate cyclase-C receptor agonist shown to significantly improve abdominal and bowel symptoms in 2 Phase 3 IBS-C trials. Aim: To evaluate the impact of linaclotide treatment on work productivity and activity impairment in IBS-C patients. Methods: Adult patients meeting modified Rome II criteria for IBS-C were randomized to oral once-daily 290-μg linaclotide or placebo for 12 weeks in 2 Phase 3 trials. The Work Productivity and Activity Impairment questionnaire for IBS-C (WPAI:IBSC), a self-administered questionnaire consisting of 6 items, was used to measure absenteeism (work hours missed due to IBS-C), presenteeism (degree IBS-C symptoms affected productivity while at work), overall work productivity loss (absenteeism + presenteeism due to IBSC), and daily activity impairment (degree IBS-C symptoms affected regular daily activities, including housework, shopping, childcare, exercising, studying) over the previous 7 days. Based on pooled Phase 3 trial data, changes from baseline to weeks 4, 8, and 12 for all 4 WPAI scores were assessed using an analysis of covariance (ANCOVA) model. Scores are represented as percentages, with higher percentages indicating greater work productivity loss and activity impairment. Results: A total of 1602 patients were randomized in the 2 Phase 3 trials. Patients included in this analysis had both baseline and at least 1 postbaseline WPAI:IBS-C assessment. Daily activity impairment was computed for all patients. Summary measures for absenteeism, presenteeism, and overall work productivity included employed patients only. Compared to placebo, linaclotide significantly reduced presenteeism, overall work productivity loss, and daily activity impairment at weeks 4, 8, and 12. A greater decrease in absenteesim was also observed for linaclotide compared to placebo at weeks 4, 8, and 12. Differences versus placebo in change from baseline to week 12 were 5.6% (p<0.0001) for presenteeism, 4.6% (p<0.0001) for overall work productivity, and 4.7% (p<0.001) for daily activity impairment (Table). Assuming a 40-hour work week, linaclotide reduced overall work productivity loss by 1.8 hours/week. Conclusions: Compared to placebo, once-daily linaclotide significantly reduced overall work productivity loss and daily activity impairment among IBS-C patients, with significant improvements seen at Week 4 and maintained through Week 12. Table. Mean WPAI Scores and Change from Baseline to Week 12

Clinical trial: lubiprostone in patients with constipation‐associated irritable bowel syndrome – results of two randomized, placebo‐controlled studies

Effective treatments for irritable bowel syndrome with constipation (IBS-C) are lacking. To assess the efficacy and safety of lubiprostone in IBS-C. A combined analysis was performed among 1171 patients with a Rome II diagnosis of IBS-C in two phase-3 randomized trials of lubiprostone 8 mcg vs. placebo twice daily for 12 weeks. Using a balanced seven-point Likert scale ranging from significantly relieved (+3), to significantly worse (-3), patients responded on their electronic diary to the question: 'How would you rate your relief of IBS symptoms over the past week compared to how you felt before you entered the study?'. The primary efficacy endpoint was the percentage of overall responders. Using an intent-to-treat analysis with last observation carried forward, a significantly higher percentage of lubiprostone-treated patients were considered overall responders compared with those treated with placebo (17.9% vs. 10.1%, P=0.001). Patients treated with lubiprostone reported a similar incidence of adverse events to those treated with placebo. The percentage of overall responders based on patient-rated assessments of IBS-C symptoms was significantly improved in patients treated with lubiprostone 8 mcg twice daily compared to those treated with placebo. Lubiprostone was well tolerated with a favourable safety profile.

Tegaserod in the treatment of irritable bowel syndrome (IBS) with constipation as the prime symptom.

Irritable bowel syndrome with constipation (IBS-C) as the predominant bowel symptom is a prevalent disorder, characterized by recurring abdominal pain/discomfort, bloating, and constipation, and imposes a significant socio-economic burden. Traditional treatments generally address just one of the multiple IBS symptoms. The efficacy and safety profile of tegaserod, a serotonin 5-HT(4) receptor agonist, has been demonstrated in several randomized, placebo-controlled, and open-label trials. This review discusses the major clinical trials of tegaserod, which have involved 8948 IBS patients. Overall, data reveal that tegaserod is an effective treatment for IBS-C, providing statistically significant relief of overall and multiple individual IBS-C symptoms (abdominal pain/discomfort, bloating, and constipation) in both placebo-controlled and "real-life" open-label settings. Repeat treatments with tegaserod were also shown to be effective, which is noteworthy given the chronic and episodic nature of IBS. Moreover, tegaserod was associated with improvements in patients' quality of life and work productivity. Data also indicate that tegaserod is well tolerated over the short-term (4 weeks), long-term (12 months), and repeated treatments. Diarrhea is the only adverse event consistently associated with tegaserod and was generally mild and transient. Overall, tegaserod has been demonstrated to offer effective and well-tolerated treatment of IBS-C, providing patients with meaningful symptom relief.

Irritable bowel syndrome medications side effects survey.

This study was conducted to determine the frequency and severity of side effects (SEs) experienced during treatment with standard medications used to treat patients with irritable bowel syndrome (IBS) with constipation (IBS-C). In January of 2002, 668 subjects responded to a survey addressed to an online panel of 25,000 physician-diagnosed IBS sufferers. Of the survey respondents, 504 had constipation as a predominant bowel habit (median age 45 years, and 88% were women). Respondents answered questions about the therapies they used to relieve their IBS symptoms and about any SEs they experienced while taking these therapies; they were also asked to rate their satisfaction with their current/past medications. To gauge IBS impact, respondents were also asked about the number of times they either visited or called their health-care provider about their IBS symptoms and approximately how many days of work or school they missed because of their IBS symptoms. Subjects reported having tried an average of 3.9 +/- 3.3 medications for their IBS-C symptoms with virtually all subjects (99%) having tried at least 1 medication. Subjects reported an average of 3.3 +/- 2.7 SEs. Nearly three quarters reported discontinuing treatment because of SEs, and many sought medical help or missed work, school, or social activities because of SEs. Traditional therapies for IBS-C, including laxatives, fiber, and stool softeners, are associated with SEs that negatively affect the lives of IBS sufferers.