Mo1275 Safety and Tolerability of Rifaximin in a Repeat Treatment Study in Subjects With IBS-D: Results From TARGET 3

patients frequently report emotions of fear and helplessness, we hypothesized that an individual's reaction to trauma may be as, if not more, important than the trauma itself in the development and severity of IBS. AIM: To compare peritraumatic experiences in IBS patients and healthy controls (HCs). METHODS: IBS patients were Rome+ and HCs were without functional gastrointestinal disorders or other chronic pain conditions. Reponses to the items addressing peritraumatic emotions and experiences (Fear, Dissociation) in IBS vs HCs were compared with Chi-square tests. Logistic regression was used to test the ability to predict group membership for IBS vs HCs. Continuous variables were compared with the Mann Whitney test. RESULTS: Participants were 368 IBS patients and 445 HCs (77.7% and 69.4% women) who reported at least one early adverse event. ETI-SR scores for the total scale and the four subscales were higher in IBS compared to HCs (mean (SD) for the total scale: 6.1(5.3) and 3.9(4.0) in IBS and HCs, p<0.0005). The proportions of participants reporting Fear and Dissociation in IBS vs HCs are shown in Figure 1. Both of these items were more frequently reported by IBS vs HCs (60.4% vs 36.7%, p<0.0005; 23.7% vs 13.0%, p<0.0005 for emotions of Fear and Dissociation, respectively) Controlling for Age and Sex, the total ETI-SR score was a significant predictor of IBS status (B=0.095, p<0.0005, Chisquare for model 66.7, p<0.0005), which is in line with previous findings. When Fear and Dissociation were added to the model, its ability to predict IBS was improved (Chi-square = 86.9, p<0.0005) and Fear was an independent predictor of IBS (B=0.691, p<0.0005). The odds ratio (95%CI) for IBS in those reporting Fear was 2.0 (1.4-2.8) compared to those who did not. Within IBS, Fear was associated with increased mean abdominal pain scores (10.0 vs 8.9, p=0.032) and number of MD visits in the prior year (p=0.021). Other associations, including in the control group are shown in Table 1. CONCLUSIONS: The association of peritraumatic fear with the development of IBS may be due to sustained effects of an enhanced stress response at the time of the traumatic event. In addition, emotions of fear and helplessness can increase the severity of IBS by amplifying the emotional response to GI symptoms Table 1: Characteristics of IBS patients and HCs with history of early adverse life events by report of peritraumatic "fear, horror or helplessness"

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Introduction: One's disposition to be attentive to present moment experiences with an open, nonreactive, non-judging attitude can be captured in the construct of trait mindfulness. This trait has been associated with positive health outcomes, and mindfulness based interventions improve symptoms in many chronic medical conditions including IBS. However, it is not clear which components of mindfulness are most important in determining positive health or resilience to illness. Aims: To determine which components of mindfulness are associated with clinical variables in Irritable Bowel Disorder (IBS). Methods: 48 Rome III+, non-meditating IBS patients (75% female, mean age=32.7+10.7yrs) were evaluated with the Five Facet Mindfulness Questionnaire (FFMQ) (see Table 1) and other clinical variables. Step-wise regression analyses examined independent relationships between individual FFMQ scales and FFMQ scale interactions and IBS Symptom Severity Scale, the Hospital Anxiety and Depression scale (HADS), fear of visceral sensations (the Visceral Sensitivity Index, VSI) as well as the Connor-Davidson Resilience Scale (CDRISC) a measure of resilience to adversity. Results: Inter-scale correlations indicated the FFMQ structure was similar in non-meditating IBS patients to published psychometric data. IBS severity was not associated with any single FFMQ scale or the FFMQ total score, but was related to the interaction of the ActAware and NonJudge scales (std beta=.383, p=.012). Those with greater present moment awareness (ActAware) had lower IBS severity but only if they also had a nonjudgmental stance toward inner experience. The only significant predictor of visceral fear was the interaction of the Observe and NonReact subscales (std beta -.375, p=.016). Lower visceral fear was predicted by an increased propensity to observe the present moment, but only in those with high non-reactivity to affect. In those with higher reactivity, greater present moment observation predicted higher visceral fear. Only the ActAware scale was significantly associated with anxiety (std beta=-.442, p=.006). Both the Describe (std. beta=.48, p=.002) and NonJudge (std. beta=.51, p=.004) scales of the FFMQ were significantly associated with self-reports of resilience to stress and illness. Conclusions: IBS severity and visceral fear are associated with specific facets of the mindfulness construct. These observations should inform future evaluation of the mechanisms of mindfulness and other psychological treatments for IBS, as well as refining cognitive theories of IBS symptom development and maintenance. Of particular importance is the finding of interactions between attention to internal sensations and how those sensations are judged as predictors of IBS severity and visceral fear. Components of mindfulness

Mo1275 Values are means (standard deviations); 1p=0.024; 2p<0.005 within group (IBS,HC); 3Over the prior week; 4 Hospital Anxiety and Depression Scale; 5Mental Health Composite Score; 6 Over the prior year for any reason

Safety and Tolerability of Rifaximin in a Repeat Treatment Study in Subjects With IBS-D: Results From TARGET 3 Anthony Lembo, Pamela Golden, Andrew C. Barrett, Enoch Bortey, Craig Paterson, William P. Forbes Background: The safety profile of rifaximin (RFX) in subjects with IBS-D has been evaluated in phase 3 studies of single, 14-day courses of therapy (TARGET 1 and 2). The aim of this study was to further examine the safety profile of RFX under conditions of repeated (up to 3 cycles) courses of therapy. Methods: Subjects with IBS-D (Rome III criteria) who responded to an open-label (OL), 2-week course of RFX 550 mg TID, and subsequently experienced a recurrence of symptoms within 18 weeks, were randomized to receive two, 2-week, doubleblind (DB), repeat treatments (RFX 550 mg TID or placebo) separated by 10 weeks. Adverse event data from the OL and DB phases are presented as the aggregate of 2-week treatment periods plus follow-up, maintenance periods. For prospective evaluation of stool culture and antibiotic susceptibility testing, all subjects participating in the study provided stool samples at the beginning and end of OL treatment, beginning and end of the first repeat treatment, and end of study (Figure). Results: Overall, 2,579 subjects were enrolled in the study. During the OL phase, 822 (32%) subjects experienced a treatment-emergent adverse event (TEAE). Nausea (52 subjects, 2%) was the only TEAE occurring in ≥2% of subjects. Abdominal pain, influenza, nasopharyngitis, sinusitis, upper respiratory tract infection, UTI, blood creatine phosphokinase increased, and headache occurred in ≥1% but <2% of subjects. TEAEs of constipation occurred in 15 subjects (0.6%). Twenty-eight (1%) subjects experienced serious TEAEs, none of which was considered related to study drug. The Table shows the most common TEAEs reported in the 636 subjects (RFX: n = 328, PBO: n = 308) who progressed to the DB repeat treatment period. Treatment-emergent AEs of constipation were reported in 1 RFX-treated subject and 3 PBO-treated subjects. Four subjects (1%) from each treatment group experienced a serious TEAE, none of which was considered related to study drug. One serious TEAE of C. difficile was reported. This patient had past history of C. diff infection and developed C. difficile in the maintenance phase (off study drug) while being treated with cephalosporin for UTI. Evaluation of stool culture and antibiotic susceptibility data indicated that neither a single rifaximin course nor up to 3 courses of therapy adversely affected bacterial sensitivity to other antibiotic classes, promoted pathogenic bacterial growth, or increased occurrence of opportunistic infections. Conclusions: No new safety signals were apparent for rifaximin under conditions of repeated courses of therapy as compared to a single, 14-day course of therapy.

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AGA Abstracts

AGA Abstracts

Disease Relevant Components of Mindfulness in Irritable Bowel Syndrome (IBS) Kirsten Tillisch, Zafar S. Gill, Jennifer S. Labus, Jean Stains, Suzanne R. Smith, Bruce D. Naliboff

Questionnaire), and general HRQOL (SF-36)]. GI symptoms were assessed using the GI Symptom Rating Scale for IBS (GSRS), and IBS-related HRQOL using the BEST questionnaire. Physician assessment of IBS symptom severity was documented using an established 4-point Likert scale (0= no symptoms, 3= disabling symptoms). Prescription of an opioid (agent, dose) was documented at initial presentation. Results: A current opioid was reported by 59 (43.1%) of IBS patients. Controlling for age and sex, opioid use was significantly related to depression (OR 2.9, 95%CI 1.3-6.8, p=0.01), anxiety (OR 3.0, 95%CI 1.3-6.9, p=0.003), and high somatization (OR 3.0, 95%CI 1.3-6.6, p=0.009). (Need to mention how many had a history of abuse here). 30 (50.8%) IBS patients with a history of abuse were on opioids, compared to 26/78 (33.3%) without abuse histories (X2=4.3, p=0.039). Despite their intended analgesic benefits, IBS patients with opioid prescriptions reported worse GI symptom severity (GSRS total: 49.0±2.3 vs 42.5±1.8, p=0.034) GI HRQOL (BEST: 103.1±33.5 vs 50.1±3.7, p=0.026) and poorer general HRQOL (50.6±2.7 vs 35.6±3.2, p<0.001). Despite patient perceptions, physician assessment of IBS symptom severity was comparable across participants, independent of opioid use (p=0.35). Conclusion: Prescription opioid use is prevalent among IBS patients, and is strongly associated with psychiatric comorbidity and history of abuse. IBS patients using prescription opioids report more severe GI symptoms, as well as poorer IBS related and general HRQOL despite physician perceptions of their clinical status. Understanding the cause-effect relationship of these observations will be paramount to the successful reduction of opioid prescriptions in FGID patients.

AGA Abstracts

Most common adverse events during double-blind phase (>3% of subjects)

Mo1278 Review of Systems and Medication Allergies Predict Presence and Severity of Functional GI Disorders (FGIDs) Pratibha Abraham, Navya D. Kanuri, Benjamin Cassell, Britt M. Gott, Billy D. Nix, C. Prakash Gyawali, Gregory S. Sayuk Figure. Study flow

Background: Functional GI disorder (FGID) manifest clinically-unexplained symptoms with an abdominal pain predominance. FGID patients have higher numbers of non-GI functional syndromes, recent somatic symptoms, and greater psychiatric comorbidity compared to non-FGID controls (Sayuk et al Clin Gastro Hep 2007). Previously it has been demonstrated that simple review of systems (ROS) checklists have predictive value in establishing FGID diagnoses (Brown JH et al J Clin Gastro 2003). FGID patients may report higher numbers of medication allergies/intolerances as part of hypersensitivity; thus this factor may serve as an additional clinical clue to FGID diagnoses. This study was conducted to assess the relationship of medication intolerances and ROS with FGID symptom severity and GI healthrelated quality of life (HRQOL). We also sought to evaluate the association of ROS and allergy reports with psychiatric comorbidity (anxiety, depression, somatization). Methods: 208 patients (156 F, 49.9±1.2 yrs) seen in a tertiary GI setting from 8/2009-5/2014 completed self-reports of ROS (51 symptoms without GI symptoms/79 with GI symptoms) and medication allergies. Validated instruments assessed mood (Beck Depression/Anxiety Inventories), somatization (PHQ-12), and general HRQOL (SF-36). GI symptoms were assessed using the GI Symptom Rating Scale (GSRS) and the B.E.S.T. questionnaire measured bowel-related HRQOL. ROME III Research Diagnostic Questions confirmed FGID diagnoses (FD and/or IBS). Results: 153 (73.6%) patients met ROME criteria for at least one FGID (110FD, 128 IBS). Compared to non-FGID GI patients, FGID subjects had twice the number of positive ROS (14.1±0.9 vs 7.0±0.8, p=0.019) but similar mean numbers of medication allergies (1.3±0.2 vs 1.0±0.2, p=0.36). Patients endorsing more than 7 ROS had a three-fold higher likelihood of a FGID diagnosis (OR 3.4, 95%CI 1.8-6.4, p<0.001). ROS correlated with depression, anxiety, and somatization (r=0.5-0.7, p<0.001 for each). ROS remained as an independent predictor of FGID in multivariate regression analysis with all psychiatric measures included (p=0.023). Controlling for age and sex, greater numbers of ROS and medication allergies both significantly predicted higher GSRS (B=0.53, p=0.002; B=3.6, p= 0.003,respectively). Only ROS predicted poorer GI HRQOL (B=0.92, p=0.004) and general HRQOL (B=-1.4, p<0.001). Conclusion: High numbers of endorsed symptoms on selfreport ROS checklists predict FGID diagnoses, and along with medication allergies are associated with more severe GI symptoms. ROS also strongly correlate with psychiatric measures; when present in high numbers, ROS and medication allergies should raise clinical suspicion of the hypersensitivity common to FGIDs.

Mo1276 Abuse Histories Predict Greater Functional GI and Pain Comorbidities in Irritable Bowel Syndrome (IBS) Patients Navya D. Kanuri, Pratibha Abraham, Steven E. Bruce, Kamila S. White, Benjamin Cassell, Britt M. Gott, Billy D. Nix, C. Prakash Gyawali, Gregory S. Sayuk Background: IBS is a common functional GI syndrome with a prominent pain component. History of physical, sexual, and/or emotional abuse is more prevalent among IBS sufferers. Previously we reported that abuse is linked to more severe and frequent IBS symptoms and poorer health related quality of life (HRQOL). If abuse experiences heighten brain neurocircuitry sensitivity to pain experiences as has been suggested (Ringel Y et al Gastroenterol 2008), this study then sought to examine the effects of an abuse history on rates of functional GI disorder (FGID) diagnoses, non-GI diagnoses, and recent pain symptoms among an IBS population; further, we aimed to determine whether experiences of multiple forms of abuse resulted in greater likelihood of developing functional GI and non-GI complaints. Methods: Consecutive GI outpatients were invited to complete ROME III Research Diagnostic Questionnaire to establish FGID criteria. Self-report questionnaires on abuse history (Life-Stress Questionnaire) were obtained, with a focus on physical, sexual, and emotional abuse. IBS patients with histories of any form of these abuse experiences were defined as IBS+/Abuse+. Recent non-GI somatic symptoms (PHQ-12), and historical somatic pain diagnoses (e.g., fibromyalgia, headache, chronic back pain) were recorded. 272 ROMEdefined IBS subjects (50.1±0.9 yrs, 81% female) were identified, and reported greater rates of abuse compared to a non-IBS comparator group (n=246): physical (18.1% vs 6.6%), sexual (15.5% vs 7.4%), and emotional (31.7% vs 16.9%) (p<0.005 for each). Results: In total, n=95 (34.9%) IBS subjects reported at least one form of abuse (IBS+/Abuse+), and n= 54 (19.8%) reported experiencing >1 form of abuse. Compared to IBS subjects without abuse histories (IBS+/Abuse-), IBS+/Abuse+ subjects had greater total numbers of ROME diagnoses (2.5±0.3 vs 2.1±0.3, p=0.10), non-GI pain diagnoses (1.9±0.2 vs. 0.9±0.08, p<0.001), and more recent somatic symptoms (9.6±0.5 vs. 7.7±0.4, p=0.001). All forms of abuse experiences imposed similar risk of functional syndromes. An additive effect of multiple forms of abuse was observed, such that greater numbers non-GI pain disorders (F=13.5, p<0.001) and somatic symptom complaints (F=5.8, p=0.001) were noted with the experience of multiple forms of abuse. This additive effect was not relevant to the number of ROME diagnoses recorded, however (F=0.69, p=0.55). Conclusions: Abuse experiences common in IBS patients are associated with reports of greater non-GI symptoms, historical somatic diagnoses, and to a lesser extent additional FGID diagnoses in IBS patients; these relationships are particularly robust when multiple forms of abuse have been experienced. These observations provide indirect evidence of an enhanced susceptibility to both GI and somatic functional disorders following abuse.

Mo1279 Durability of Benefit in IBS-D Patients Responding to a 2-Week Course of Rifaximin: Results From TARGET 3 Mark Pimentel, Lin Chang, Anthony Lembo, Andrew C. Barrett, Jing Yu, Enoch Bortey, Craig Paterson, William P. Forbes Background: Rifaximin (RFX) has demonstrated efficacy in the treatment of IBS-D symptoms in 2 large, randomized, controlled trials of 12 weeks duration following a single 2-week treatment. Current evidence suggests that the durability of effect may persist beyond the 12 weeks evaluated in the pivotal studies. The objective of this analysis was to more accurately characterize the duration of benefit in patients who respond to an initial course of rifaximin therapy. Methods: Patients with IBS-D (Rome III criteria) with average symptom severity scores of ≥ 3 for IBS-related abdominal pain (AP, scale 0-10) and bloating (scale 0-6), with ≥ 2 stools with Bristol Stool Scale (BSS) Type 6 (loose) or 7 (watery) during the 7-day baseline were entered into the open-label phase (OL) of the trial (Figure 1). In OL, all patients were treated with RFX 550 mg TID for 2 weeks, followed by a 4-week treatmentfree follow-up period to assess response to treatment. A responder was defined as meeting weekly response criteria for both AP (≥30% decrease from baseline in mean weekly pain score) and stool consistency (SC) (≥50% decrease from baseline in number of days/week with BSS Type 6 or 7) for ≥2 of 4 weeks. Responders in the OL phase were subsequently followed until relapse (up to 18 additional weeks), upon which they were randomized to receive 2 double-blind, placebo-controlled, repeat treatments (RFX 550 mg TID or placebo) separated by 10 weeks. Relapse was defined as loss of response for either AP OR SC for ≥ 3 out of a 4 week period during the 18-week maintenance phase. Results: Of 2579 patients (mean age: 46.4; 68% female; mean daily bowel movements: 3.9; mean daily AP score: 5.5; mean daily SC score: 5.6) who received OL RFX, 2331 were evaluable for efficacy, of which 1074 (46%) were responders based on the composite endpoint of AP and SC. This initial

Mo1277 Clinical Factors Associated With Opioid Prescription Use Among Irritable Bowel Syndrome (IBS) Patients Navya D. Kanuri, Pratibha Abraham, Benjamin Cassell, Steven E. Bruce, Kamila S. White, Britt M. Gott, Billy D. Nix, C. Prakash Gyawali, Gregory S. Sayuk Background: Prescription of opioids for non-cancer pain indications is increasing dramatically in the US, without evidence for established benefit in many of these settings (Eriksen et al, Pain 2006). As chronic abdominal pain is a predominant symptom in IBS, this patient population may be particularly at risk for treatment with opioids (Rx). Opioids paradoxically may worsen IBS symptoms via alterations in intestinal transit, upregulation of pain pathways and development of narcotic bowel syndrome. We evaluated the relationship between opioid prescriptions and self-reported or physician assessed IBS symptoms in determining clinical and psychological factors associated with prescription opioid use in IBS patients. Methods: 137 clinically-diagnosed IBS patients (112 F, 49.9±1.2 yrs) seen in a tertiary GI setting over a 5 years completed questionnaires [mood (Beck Depression/Anxiety Inventories), somatization (PHQ-15), abuse history (physical, sexual, and/or emotional on Life-Stress

AGA Abstracts

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