Mollie J. Baird

Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-Week, Randomized, Double-blind, Placebo-Controlled Trial to Evaluate Efficacy and Safety

OBJECTIVES:Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide treatment in patients with irritable bowel syndrome with constipation (IBS-C) over 26 weeks.METHODS:This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 μg of oral linaclotide once daily for a 26-week treatment period. The primary and the secondary efficacy assessments were evaluated over the first 12 weeks of treatment. Primary end points included the Food and Drug Administrations (FDAs) end point for IBS-C (responder: a patient who reported (i) improvement of ≥30% from baseline in average daily worst abdominal pain score and (ii) increase of ≥1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for ≥6/12 weeks) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored.RESULTS:In all, 804 patients (mean age=44 years, female=90%, white=78%) were evaluated; 33.7% of linaclotide-treated patients were FDA end point responders, vs. 13.9% of placebo-treated patients (P<0.0001) (number needed to treat=5.1, 95% confidence interval (CI): 3.9, 7.1). The pain responder criterion of the FDA end point was met by 48.9% of linaclotide-treated patients vs. 34.5% of placebo-treated patients (number needed to treat=7.0, 95% CI: 4.7, 13.1), and the CSBM responder criterion was met by 47.6% of linaclotide-treated patients, vs. 22.6% of placebo patients (number needed to treat=4.0, 95% CI: 3.2, 5.4). Remaining primary end points (P<0.0001) and all secondary end points (P<0.001), including abdominal pain, abdominal bloating, and bowel symptoms (SBM and CSBM rates, Bristol Stool Form Scale (BSFS) score, and straining), were also statistically significantly improved with linaclotide vs. placebo. Statistically significant differences from placebo were observed for responder and continuous end points over 26 weeks of treatment. AE incidence was similar between treatment groups, except for diarrhea, which caused discontinuation in 4.5% of linaclotide patients vs. 0.2% of placebo patients.CONCLUSIONS:Linaclotide 290 μg once daily significantly improved abdominal and bowel symptoms associated with IBS-C over 26 weeks of treatment.

Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation.

BACKGROUND & AIMS Linaclotide, a minimally absorbed, 14-amino acid peptide agonist of guanylate cyclase-C, has shown benefit in a proof-of-concept study for the treatment of patients with irritable bowel syndrome (IBS) with constipation (IBS-C). We assessed the efficacy and safety of linaclotide at a daily dose range of 75-600 μg in IBS-C. METHODS We performed a randomized, double-blind, multicenter, placebo-controlled study of 420 patients with IBS-C given oral linaclotide at doses of 75, 150, 300, or 600 μg or placebo once daily for 12 weeks. End points included change from baseline in daily bowel habits, daily abdominal symptoms, and weekly global assessments, in addition to responder criteria. RESULTS All doses of linaclotide significantly improved bowel habits, including frequency of spontaneous bowel movements and complete spontaneous bowel movements (primary end point), severity of straining, and stool consistency. Abdominal pain was significantly reduced from baseline, compared with placebo; mean changes in abdominal pain (assessed on a 5-point scale) from baseline were -0.71, -0.71, -0.90, and -0.86 for linaclotide doses of 75, 150, 300, and 600 μg, respectively, compared with -0.49 for placebo. Likewise, most doses of linaclotide significantly improved other abdominal symptoms, including discomfort and bloating, and global measures of IBS-C compared with placebo. Effects were observed within the first week and were sustained throughout 12 weeks of treatment. Except for diarrhea, the incidence of adverse events was similar between placebo and linaclotide groups. CONCLUSIONS Linaclotide, across a wide range of doses, significantly improved symptoms of IBS-C, including abdominal pain and bowel symptoms. Diarrhea was the only dose-dependent adverse event and was usually of mild or moderate severity.

An evaluation of the FDA Responder Endpoint for IBS‐C clinical trials: analysis of data from linaclotide Phase 3 clinical trials

Our objective was to evaluate the performance of the Food and Drug Administration (FDA) Responder Endpoint for clinical trials in IBS‐C, using data from two large Phase 3 clinical trials of linaclotide. The FDA interim endpoint requires that, for 50% of trial weeks, patients report ≥30% decrease in Abdominal Pain at its worst and (in the same week) an increase in Complete Spontaneous Bowel Movements (CSBMs) of ≥1 from baseline.

Assessment of treatment response in chronic constipation clinical trials

Background While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptoms directly related to bowel movements), abdominal symptoms are also prevalent among patients. The United States Food and Drug Administration’s (FDA’s) guidance on the use of patient-reported outcome measures to support product approvals or labeling claims recommends that endpoints be developed with direct patient input and include all symptoms important to patients. Aim To identify a comprehensive set of CC symptoms that are important to patients for measurement in clinical trials. Methods Following a targeted literature review to identify CC symptoms previously reported by patients, 28 patient interviews were conducted consistent with the FDA’s guidance on patient-reported outcomes. Subsequent to open-ended questions eliciting descriptions of all symptoms, rating and ranking methods were used to identify those of greatest importance to patients. Results All 67 studies reviewed included bowel symptoms; more than half also addressed at least one abdominal symptom. Interview participants reported 62 potentially distinct concepts: 12 bowel symptoms; 21 abdominal symptoms; and 29 additional symptoms/impacts. Patients’ descriptions revealed that many symptom terms were highly related and/or could be considered secondary to CC. The rating and ranking task results suggest that both bowel (for example, stool frequency and consistency) and abdominal symptoms (for example, bloating, abdominal pain) comprise patients’ most important symptoms. Further, improvements in both bowel and abdominal symptoms would constitute an improvement in patients’ CC overall. Conclusion Abdominal symptoms in CC patients are equal in relevance to bowel symptoms and should also be addressed in clinical trials to fully evaluate treatment benefit.

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

Tu1381 Effects of 26 Weeks of Linaclotide Treatment on Adequate Relief and IBS Severity in Patients With Irritable Bowel Syndrome With Constipation

Introduction There have been few long-term studies evaluating treatments for IBS. Linaclotide (LIN), a 14 amino acid, minimally absorbed, guanylate cyclase C agonist (GCCA), was evaluated in 2 Phase 3 trials in patients (pts) with IBS-C, including a double-blind trial with an extended 26 wk Treatment Period, in which statistically significant improvements in abdominal pain and complete spontaneous bowel movement (CSBM) frequency were sustained for up to 26 wks. In a subsequent analysis of this study, we assessed the effects of 26 wks of LIN treatment on adequate relief and IBS severity and the relationship between long-term improvement in adequate relief with improvements in abdominal pain and CSBM frequency. Methods Adult pts with IBS-C (Rome II criteria) were randomised to LIN 290 μg or placebo (PBO) qd po for 26 wks. Endpoints included daily pt rating of abdominal pain at its worst during the previous 24 h on an 11-point scale (0 = none, 10 = very severe) and CSBM frequency. Pts also rated adequate relief of IBS symptoms (yes/no) and IBS severity (5-point scale: 1 = none, 5 = very severe) weekly. An Adequate Relief Responder was defined as a pt with adequate relief of IBS symptoms for ≥13 of the 26 wks of the Treatment Period. Spearman correlations were performed for Adequate Relief Responders and individual symptom improvement. Results The study included 401 LIN- and 403 PBO-treated pts. With LIN, 49% of pts were Adequate Relief Responders vs 25% of PBO pts (difference 24.1; p Conclusion Significantly more LIN pts vs PBO pts reported adequate relief of IBS symptoms and improvement of IBS severity during 26 wks of treatment. Gains in the % of pts reporting adequate relief correlated strongly with improvements in abdominal pain and CSBM frequency. Supported by Ironwood Pharmaceuticals Inc and by Forest Laboratories Inc. Editing assistance was provided by Complete Medical Communications, funded by Almirall. Disclosure of Interest E. Quigley Speaker bureau with: Danone, Janssen, Procter and Gamble, sanofi-aventis, Shire and Yakult, Conflict with: Advisory boards for Almirall, Ironwood, Janssen, Norgine, Salix and Shire/Movetis, W. Chey Consultant for: Ironwood Pharmaceuticals and Forest Research Institute, B. Lavins Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, M. Baird Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, D. Fitch Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, X. Hao Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, K. Shi Employee of: Forest Laboratories, M. Currie Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, H. Schneier Shareholder of: Forest Laboratories, Employee of: Forest Laboratories, J. Johnston Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals

Psychometric validation of patient-reported outcome measures assessing chronic constipation

Background Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration’s guidance on patient-reported outcomes. Aim Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures. Study methods Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed. Results The CC Symptom Severity Measures demonstrated satisfactory test–retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change. Conclusion In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.

Psychometric validation of symptom severity measures in irritable bowel syndrome with constipation

Historically, measures of symptom severity of irritable bowel syndrome with constipation (IBS‐C) in clinical trials have not met the evidence requirements described in the FDA guidance on patient‐reported outcomes (PROs), which describes the evidentiary requirements and review criteria for patient‐reported outcome measures intended to support product approval or labelling claims.

PWE-167 Effect Of Linaclotide On Ibs-qol Sexual Subscale Scores In Patients With Irritable Bowel Syndrome With Constipation: Results From 2 Phase 3 Trials

Introduction Linaclotide is a minimally absorbed guanylate cyclase-C agonist approved for treatment of IBS with constipation (IBS-C). IBS often results in diminished quality of life (QOL), including decreased sexual desire and activity. This post-hoc analysis aimed to determine if linaclotide treatment improved IBS-QOL sexual subscale scores in IBS-C patients, compared to placebo. Methods Data from 2 randomised, double-blind Phase 3 linaclotide trials in IBS-C were pooled. The IBS-QOL was administered at baseline and Week 12. The sexual subscale includes items on difficulty with sexual activity and reduced sexual desire, both rated on a 5-point scale (1=not at all, 2=slightly, 3=moderately, 4=quite a bit, 5=extremely/a great deal); the sum of both items is scaled to 0 (worst) to 100 (best). Changes in the scores from baseline to Week 12 were compared for linaclotide- vs placebo-treated patients in the intent-to-treat (ITT) population and the Impaired Sexuality (IS) subgroup (baseline sexual subscale scores ≤50). Results Of 1598 ITT patients with baseline sexual subscale scores, 522 (33%) had a score ≤50 indicating significant impact of IBS on sexual desire and activity (females: 484/1439 [34%]; males: 38/159 [24%]). At Week 12, linaclotide significantly improved change-from-baseline sexual subscale scores vs placebo in the ITT population and IS subgroup (Table, p < 0.001 for both). Although baseline scores for males were higher (better) than for females, improvement vs placebo for males was similar to females in the ITT population and greater for the IS subgroup. However, the male sample size was too small to establish statistical significance. Abstract PWE-167 Table 1 IBS-QOL sexual subscale results Placebo (ITT) Linaclotide (ITT) Change from baseline Δ P -value (ITT) Placebo (IS) Linaclotide (IS) Change from baseline Δ P-value (IS) Overall (n) 795 803 5.2 <0.0001* 249 273 7.2 0.0007* Baseline 68.9 (31.9) 66.9 (30.9) 27.2 (17.8) 29.5 (17.7) Week 12 79.7 (25.9) 83.1 (23.6) 57.8 (29.9) 67.9 (28.1) Females (n) 706 733 5.2 <0.0001* 228 256 6.7 0.0016* Baseline 68.0 (32.3) 66.1 (31.1) 26.6 (17.8) 29.5 (17.8) Week 12 79.8 (25.8) 83.2 (23.4) 58.5 (30.2) 68.6 (27.7) Males (n) 89 70 4.2 0.3129* 21 17 10.2 0.2389* Baseline 76.3 (28.1) 74.5 (28.7) 32.7 (16.5) 30.1 (17.7) Week 12 78.9 (26.7) 81.5 (26.0) 50.0 (25.7) 57.8 (33.2) Data are mean (SD) * P-values based on change-from-baseline treatment difference for linaclotide vs placebo (ANCOVA) Conclusion Linaclotide treatment significantly improves IBS-QOL sexual subscale scores in IBS-C patients compared with placebo, in both the total population and in patients with impaired sexuality at baseline. Study funded by Forest Laboratories, Inc., and Ironwood Pharmaceuticals, Inc. Disclosure of Interest M. Currie Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, S. Shiff Shareholder of: Forest Research Institute, Employee of: Forest Research Institute, X. Hao Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, R. Carson Shareholder of: Forest Research Institute, Employee of: Forest Research Institute, M. Baird Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, J. Johnston Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals.

Su2065 Qualitative Assessment of Symptom Experience in Patients With Irritable Bowel Syndrome for the Development of Patient-Reported Outcome Instruments

for the Development of Patient Reported Outcome Instruments Mollie J. Baird, MPH1; Robyn T. Carson, MPH2, Claire Ervin, MPH3; Lin Chang, MD4; Brennan Spiegel, MD4; Nancy J. Norton5; Jeffrey Lackner, PsyD6; Karen Lasch, MD7; and Sheri E. Fehnel, PhD3 on Behalf of the Critical Path Institute PRO Consortiums Irritable Bowel Syndrome Working Group 1Ironwood Pharmaceuticals, Cambridge, MA, USA; 2Forest Research Institute, Jersey City, NJ, USA; 3RTI Health Solutions, Research Triangle Park, NC, USA; 4Division of Digestive Diseases, University of California, Los Angeles, CA, USA; 5International Foundation for Functional Gastrointestinal Disorders, Milwaukee, WI, USA; 6University of Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY, USA; 7Takeda Pharmaceuticals, Chicago, IL, USA