Xinming Hao

Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial.

Background Abdominal bloating is a common and bothersome symptom of chronic idiopathic constipation. The objective of this trial was to evaluate the efficacy and safety of linaclotide in patients with chronic idiopathic constipation and concomitant moderate-to-severe abdominal bloating. Methods This Phase 3b, randomized, double-blind, placebo-controlled clinical trial randomized patients to oral linaclotide (145 or 290 μg) or placebo once daily for 12 weeks. Eligible patients met Rome II criteria for chronic constipation upon entry with an average abdominal bloating score ≥5 (self-assessment: 0 10-point numerical rating scale) during the 14-day baseline period. Patients reported abdominal symptoms (including bloating) and bowel symptoms daily; adverse events were monitored. The primary responder endpoint required patients to have ≥3 complete spontaneous bowel movements/week with an increase of ≥1 from baseline, for ≥9 of 12 weeks. The primary endpoint compared linaclotide 145 μg vs. placebo. Results The intent-to-treat population included 483 patients (mean age=47.3 years, female=91.5%, white=67.7%). The primary endpoint was met by 15.7% of linaclotide 145 μg patients vs. 7.6% of placebo patients (P<0.05). Both linaclotide doses significantly improved abdominal bloating vs. placebo (P<0.05 for all secondary endpoints, controlling for multiplicity). Approximately one-third of linaclotide patients (each group) had ≥50% mean decrease from baseline in abdominal bloating vs. 18% of placebo patients (P<0.01). Diarrhea was reported in 6% and 17% of linaclotide 145 and 290 μg patients, respectively, and 2% of placebo patients. AEs resulted in premature discontinuation of 5% and 9% of linaclotide 145 μg and 290 μg patients, respectively, and 6% of placebo patients. Conclusions Once-daily linaclotide (145 and 290 μg) significantly improved bowel and abdominal symptoms in chronic idiopathic constipation patients with moderate-to-severe baseline abdominal bloating; in particular, linaclotide significantly improved abdominal bloating compared to placebo, an important finding given the lack of agents available to treat abdominal bloating in chronic idiopathic constipation patients. Trial Registration ClinicalTrials.gov NCT01642914

The impact of abdominal pain on global measures in patients with chronic idiopathic constipation, before and after treatment with linaclotide: a pooled analysis of two randomised, double-blind, placebo-controlled, phase 3 trials

Few clinical trials in chronic idiopathic constipation (CIC) patients have evaluated abdominal symptom severity and whether CIC patients with abdominal symptoms respond similarly to patients with limited abdominal symptoms.

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

Sa2008 Efficacy and Safety of Linaclotide in Chronic Idiopathic Constipation Patients With Abdominal Bloating: Phase 3b Trial Results

Colonic motor patterns, which might become biomarkers of colonic dysmotility in constipation, are still poorly defined in humans but have been clarified including the role of myogenic, neurogenic and interstitial cells of Cajal (ICC) control systems in the rat, mouse and guinea pig. The purpose of this study was to explore the characteristics of colonic motor patterns in 8 healthy volunteers and 22 patients with chronic constipation by high-resolutionmanometry (HRM). A 36-channel Unisensor solid-state probe, 1 cm spaced, was fixed at the transversedistal colon by colonoscopy for 6-8 hours manometry recording with Medkinetic acquisition software. After 60 min baseline recording, a yogurt meal (460 g, 1400 kJ) was given to observe the gastro-colonic reflex for 90 min, thereafter 2 mg prucalopride was given to evaluate short-term effects. Results: 1) Unique to HRM recordings were the clearly definable, distinguishable and quantifiable simultaneous and propulsive contractions which all had superimposed haustral contractions; distinct from any animal model. 2) In healthy volunteers, common motor patterns included simultaneous contractions (duration of 1-3 s, 40 100 mmHg, frequency 0.5-1.7 cpm), propulsive contractions including high amplitude propulsive contractions (HAPCs; 100-250 mmHg; figure), and stationary haustral contractions (30150 mmHg) that were often rhythmic at the ICC pacemaker frequency (3 cpm). The yogurt meal and 2 mg prucalopride promoted propulsive contractions, and decreased simultaneous contractions from 7 to 2 per 30 min recording. Eight HAPCs were observed in 3 cases, with propagating distances of 8-36 cm, amplitudes of 100-220 mmHg, velocity of 53 mm/s, several HAPCs were repetitive with intervals of 60-150 sec. HAPCs usually occurred without other patterns although it happened once in between 2 simultaneous contractions. 3) In patients with chronic constipation, simultaneous and retrograde-propagating contractions of low amplitude were the main patterns, no HAPCs were observed. Simultaneous contractions (duration 1-3 s, 30 mm Hg, frequency 0.4 -1.1 cpm) were significantly promoted by yogurt (from 5 to 16 episodes / 30 min). Retrograde contractions were increased after yogurt and prucalopride, with propagating distances of 8-21 cm, 10-60 mmHg, velocity of 61 mm/s and intervals of 60-150 sec. This did not occur in healthy volunteers. 4) Flatulence was associated with simultaneous contractions; yogurt increased the episodes of flatulence in both patients and healthy volunteers. In conclusion, rhythmic low amplitude simultaneous contractions and retrograde contractions, abundance of low amplitude rhythmic haustral contractions and failure to induce HAPCs characterized chronic constipation, suggestive of enhancement of local myogenic activity and dysfunctional neurogenic control systems of propulsion.

PTH-136 Two years on linaclotide: tolerability and treatment satisfaction in patients with irritable bowel syndrome with constipation with and without diarrhoea

Introduction Linaclotide (LIN) has been shown to improve abdominal pain and stool frequency and was well tolerated in Phase 3 clinical trials of patients (pts) with irritable bowel syndrome with constipation (IBS-C). Here we evaluate the most common LIN adverse event (AE), diarrhoea, and assess tolerability and treatment satisfaction (Tx sat) in IBS-C pts who rolled over (RO) from a Phase 3 trial into a long-term study (LTS) of LIN. Method Pts meeting modified Rome II IBS-C criteria were randomised to oral 290 µg LIN or placebo daily in a 6 month Phase 3 trial. RO pts completed Phase 3 and entered an open-label 18 month LTS. Tx sat (not at all, a little, moderately, quite, very) and AEs, including any reports of diarrhoea, were recorded at all study visits; AE severity was assessed by the investigator based on pt description. In the LTS, pts could interrupt, reduce (145 µg) or withdraw from dosing due to AEs. Tx sat was assessed in pts with and without diarrhoea. Abstract PTH-136 Table 1 Severity of diarrhoea AEs (LTS), n (% of pts with diarrhoea AEs) [N=171] Mild Moderate Severe 80 (46.8) 81 (47.4) 10 (5.8) Results Of 535 IBS-C RO pts in the LTS, 79% had ≥1 AE; 45 pts (8%) withdrew due to an AE; 24 pts (4.5%) reported ≥1 serious AE (SAE). Diarrhoea, the most common AE (171 pts; 32%; 0.29/pt-year), was mostly mild or moderate in severity and led to withdrawal in 18 pts (3%) [Table 1]. There were no diarrhoea-related SAEs. 131 pts (24%) decreased and/or interrupted their LIN dose due to diarrhoea; the majority of these pts continued in the study (Table 2). Pts averaged at least moderate Tx sat; >70% of pts were moderately to very satisfied with LIN treatment regardless of whether they had diarrhoea (figure 1). Abstract PTH136 Figure 1 Conclusion During up to 2 years on LIN, IBS-C pts were moderately to quite satisfied with treatment on average. Diarrhoea AEs were generally mild or moderate in severity and infrequently led to study withdrawal. TX sat was similar in LIN-treated pts who did and did not report diarrhoea. LIN was well tolerated. Disclosure of Interest H. Schneier: None Declared, S Shiff Conflict with: Allergan plc, Conflict with: Allergan plc, X Hao Conflict with: Ironwood Pharmaceuticals, J Chickering Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals and Allergan plc, Conflict with: Ironwood Pharmaceuticals, C Kurtz Conflict with: Ironwood Pharmaceuticals, M Currie Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals, J Johnston Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals

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.

PWE-029 Characterisation and Association of Abdominal Pain With Anxiety or Depression in Patients with Irritable Bowel Syndrome with Constipation (IBS-C): Abstract PWE-029 Table

Introduction The Short-Form McGill Pain Questionnaire (SF-MPQ-2) assesses and characterises pain. It consists of 22 items (rated from 0 = none to 10 = worst possible) in 4 subscales (continuous pain, intermittent pain, neuropathic pain [sensory descriptors], and affective descriptors [emotional aspects of pain, eg cruel/exhausting]). The SF-MPQ-2 has not yet been validated in abdominal pain and, therefore, its use in functional gastrointestinal disorders like IBS is limited. Also, little is known about pain quality in IBS. We used the SF-MPQ-2 to characterise baseline abdominal pain in IBS-C and to determine whether subscale scores were associated with significant baseline anxiety or depression. Methods Over a 2-wk baseline period in 2 Phase 3 trials of linaclotide (LIN), patients (pts) with IBS-C (Rome II criteria; N = 1523) rated daily their worst abdominal pain over the past 24 h on an 11-point scale (0 = none, 10 = very severe) and completed the SF-MPQ-2. Summary statistics were calculated for each SF-MPQ-2 item and subscale. Pts were grouped by their highest-scored pain subscale and the pain subscale reported by the highest % of pts was defined as the predominant pain type. Association of each subscale with baseline abdominal pain score was determined by ANCOVA. Baseline anxiety and depression were assessed on the Hospital Anxiety and Depression Scale (HADS-A and HADS-D); pts were categorised as normal/borderline (0–10) or abnormal (11–21). Association of each subscale with abnormal HADS was analysed by logistic regression. Results Continuous pain was the predominant pain type (77% of pts); the item with the highest average score in this subscale was cramping pain. Baseline abdominal pain score was significantly associated with McGill continuous pain (p < 0.0001), intermittent pain (p = 0.004) and affective descriptors (p = 0.012), but not with neuropathic pain (p = 0.526). Only the affective descriptors subscale was significantly associated with abnormal HADS score (Table). Abstract PWE-029 Table Odds ratio Abnormal HADS Pain subscale Point estimate 95% CI p a HADS-A Continuous 1.04 0.96, 1.13 0.35 Intermittent 0.96 0.89, 1.04 0.33 Neuropathic 1.00 0.92, 1.09 0.99 Affective descriptors 1.15 1.07, 1.23 < 0.0001 HADS-D Continuous 1.11 0.94, 1.30 0.23 Intermittent 0.92 0.80, 1.05 0.21 Neuropathic 1.12 0.97, 1.29 0.12 Affective descriptors 1.24 1.10, 1.41 < 0.001 aWald χ2 test Conclusion These data indicate that continuous pain is predominant in IBS-C and that anxiety and depression are related to the emotional response to pain, not to pain itself. Support: Ironwood Pharmaceuticals Inc & Forest Laboratories Inc. Editing: CMC 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, B. Lavins Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, S. Shiff Shareholder of: Forest Laboratories, Employee of: Forest Laboratories, K. Shi Employee of: Forest Laboratories, X. Hao Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, C. Kurtz Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, 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

PWE-027 Mediation Analysis Supports a Direct Effect of Linaclotide (LIN) on Abdominal Pain (AP) Relief Independent of Constipation Improvement

Introduction LIN, a 14-amino-acid, minimally-absorbed guanylate cyclase C agonist (GCCA), significantly improved AP and complete spontaneous bowel movements (CSBMs) vs placebo (PBO) in 2 Phase 3 IBS-C trials. Recurrent AP in IBS-C may arise from increased visceral hypersensitivity exacerbated by constipation. Relative direct and mediated (increasing CSBMs) LIN effects on AP improvement are unknown. We estimated the direct effect of LIN on improving AP by controlling for a concurrent increase in CSBMs. Methods Patients (pts) with IBS-C (Rome II criteria) were randomised to LIN 290 µg po or PBO for 26 wks in a Phase 3 trial. Pts reported abdominal and bowel symptoms, and rescue medication use daily. Percent improvement from baseline in AP scores was analysed via multilevel mediation analysis to estimate the proportion of the LIN treatment effect attributable to increased CSBMs. CSBMs occurring on the reported AP score day and the previous 6 days were mediation variables. Analysis was performed for Wks 13–26, when LIN and PBO effects on AP were generally constant. An additional analysis summarised AP improvement on a particular day (2-way CSBM stratification: days since last CSBM [0, 1, 2, ≥3 days] and CSBMs in previous 3 days [0, 1, 2, ≥3 CSBMs]). Results Mediation analysis showed the 20% treatment effect of LIN (48%) on AP above PBO effect (28%) resulted from a combined direct effect (18%) on AP and indirect effect (2%) mediated by increasing CSBMs. SBMs without a sense of complete evacuation and BMs with rescue medication use did not increase the mediated LIN pain effect. The 2-way CSBM stratification analysis showed improved AP was influenced by time since last CSBM and no. of recent CSBMs (Table). Consistent with a predominant direct LIN effect on AP (per mediation analysis), in each table cell, LIN-treated pts had more AP relief than PBO pts when controlling for CSBM factors. Percent Improvement in AP Stratified by No. of Recent CSBMs and Time Since Last CSBM by Treatment Group (LIN/PBO [LIN-PBO difference]). Abstract PWE-027 Table Days since last CSBM, n CSBMs in prior 3 days, n 0 (CSBM that day) 1 2 3+ 0 45/25 [20] 1 58/43 [16] 61/37 [24] 60/40 [20] 51/38 [14] 2 74/56 [19] 72/54 [17] 65/56 [9] 57/39 [18] 3+ 76/67 [9] 76/60 [16] 76/68 [8] 74/48 [25] ITT Popn, Wks 13–26, median values (includes pts with multiple values in a particular cell) Conclusion This analysis supports the hypothesis that LIN has direct effects on AP (over PBO), and that AP effects are mediated to a lesser extent by increasing CSBM frequency. Support: Ironwood Pharmaceuticals Inc & Forest Laboratories Inc. Editing: CMC funded by Almirall Disclosure of Interest J. MacDougall Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, D. Mackinnon Consultant for: Ironwood Pharmaceuticals, B. Lavins Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, A. Lembo Consultant for: Ironwood Pharmaceuticals and Forest Laboratories, S. Shiff Shareholder of: Forest Laboratories, Employee of: Forest Laboratories, X. Hao Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, M. Currie Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, J. Johnston Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals

Sa1421 The Effect of Comorbid Psychological Distress on Baseline Irritable Bowel Syndrome With Constipation Symptoms and Response to Linaclotide Treatment

Introduction: There is evidence to suggest that comorbid psychological distress can influence symptoms and the response to therapy in IBS patients. Linaclotide is a guanylate cyclaseC agonist that has been shown to improve the symptoms of IBS with constipation (IBS-C). Aim: To assess the influence of comorbid anxiety and depression on baseline IBS-C symptom severity and response to therapy with linaclotide using the Hospital Anxiety and Depression Scale (HADS). Methods: HADS consists of 14 statements that patients rate based on their experience over the previous week: 7 related to anxiety (HADS-A) and 7 related to depression (HADS-D). Based on possible scores of 0-21, patients from 2 Phase 3 IBS-C trials of linaclotide (pooled data) were categorized as normal (0-7), borderline (8-10), or abnormal (11-21) for HADS-A and HADS-D. Analyses by HADS category included percent of patients in each category (baseline and post-treatment), demographics, baseline symptom scores, efficacy, and treatment-emergent adverse events (TEAEs). P-values comparing linaclotide vs placebo were determined using an analysis of covariance (ANCOVA) model. A logistic analysis using stepwise variable selection was performed to identify demographic and baseline characteristics that are associated with an abnormal HADS score. Results: At baseline, 25% and 22% of patients were categorized as Borderline and Abnormal for anxiety and 10% and 6% were similarly categorized for depression; proportions of patients with comorbid anxiety and depression were similar between treatment groups. Of the demographic and baseline characteristics evaluated, only IBS severity, McGill subscale of affective descriptors, and age >65 (HADS-A only) were associated with abnormal HADS-D and HADS-A (Table 1). Patients with abnormal HADS tended to have higher baseline abdominal symptom scores vs patients categorized as normal, particularly for HADS-D. Mean changes from baseline to week 12 in all abdominal and bowel symptoms were statistically significant for linaclotide vs placebo in all HADS categories, except abdominal symptoms in patients categorized as abnormal for HADS-D (which had similar treatment differences but notably smaller subgroup sample size; Table 2). Diarrhea was the most common TEAE among linaclotide patients in all HADS categories, ranging from 16-26%. Conclusions: Almost half of the study population had some degree of anxiety but only 16% had evidence of depression. Baseline anxiety had little effect on the end of treatment score or magnitude of response for abdominal symptoms. Though patients with baseline depression tended to have higher abdominal symptom scores at baseline and at the end of treatment with linaclotide, the magnitude of response was not influenced by comorbid depression. Baseline anxiety or depression did not influence the response to linaclotide for bowel symptoms. Table 1. Demographics and Baseline Characteristics Associated with Abnormal HADS (IBS-C Patients)

Mo1858 Characterization and Association of Abdominal Pain With Anxiety or Depression in Patients With Irritable Bowel Syndrome With Constipation

Introduction The Short-Form McGill Pain Questionnaire (SF-MPQ-2) assesses and characterises pain. It consists of 22 items (rated from 0 = none to 10 = worst possible) in 4 subscales (continuous pain, intermittent pain, neuropathic pain [sensory descriptors], and affective descriptors [emotional aspects of pain, eg cruel/exhausting]). The SF-MPQ-2 has not yet been validated in abdominal pain and, therefore, its use in functional gastrointestinal disorders like IBS is limited. Also, little is known about pain quality in IBS. We used the SF-MPQ-2 to characterise baseline abdominal pain in IBS-C and to determine whether subscale scores were associated with significant baseline anxiety or depression. Methods Over a 2-wk baseline period in 2 Phase 3 trials of linaclotide (LIN), patients (pts) with IBS-C (Rome II criteria; N = 1523) rated daily their worst abdominal pain over the past 24 h on an 11-point scale (0 = none, 10 = very severe) and completed the SF-MPQ-2. Summary statistics were calculated for each SF-MPQ-2 item and subscale. Pts were grouped by their highest-scored pain subscale and the pain subscale reported by the highest % of pts was defined as the predominant pain type. Association of each subscale with baseline abdominal pain score was determined by ANCOVA. Baseline anxiety and depression were assessed on the Hospital Anxiety and Depression Scale (HADS-A and HADS-D); pts were categorised as normal/borderline (0–10) or abnormal (11–21). Association of each subscale with abnormal HADS was analysed by logistic regression. Results Continuous pain was the predominant pain type (77% of pts); the item with the highest average score in this subscale was cramping pain. Baseline abdominal pain score was significantly associated with McGill continuous pain (p Conclusion These data indicate that continuous pain is predominant in IBS-C and that anxiety and depression are related to the emotional response to pain, not to pain itself. Support: Ironwood Pharmaceuticals Inc & Forest Laboratories Inc. Editing: CMC 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, B. Lavins Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, S. Shiff Shareholder of: Forest Laboratories, Employee of: Forest Laboratories, K. Shi Employee of: Forest Laboratories, X. Hao Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, C. Kurtz Shareholder of: Ironwood Pharmaceuticals, Employee of: Ironwood Pharmaceuticals, 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