AGA Abstracts 784 VELUSETRAG IMPROVES GASTOPARESIS BOTH IN SYMPTOMS AND GASTRIC EMPTYING IN PATIENTS WITH DIABETIC OR IDIOPATHIC GASTROPARESIS IN A 12-WEEK GLOBAL PHASE 2B STUDY Thomas Abell, Braden Kuo, Tuba Esfandyari, Daniel Canafax, Roberto Camerini, Maria Grimaldi, Giuseppe C. Viscomi, Cecilia Renzulli, Kefei Zhou, Deanna Nguyen, Chris Barnes, Richard W. McCallum Purpose: Velusetrag (VEL) is an oral, highly selective 5-hydroxytryptamine receptor 4 agonist with demonstrated prokinetic effects throughout the gastrointestinal tract. This study evaluated the effects of VEL on symptoms and gastric emptying in patients with diabetic or idiopathic gastroparesis. Methods: Patients with delayed gastric emptying and gastroparesis symptoms (Gastroparesis Cardinal Symptom Index [GCSI] total score ≥2.5 points at baseline) and hemoglobin A1c (HbA1c) <11% (diabetics) were randomized in 4 parallel groups to VEL 5, 15, or 30 mg, or placebo administered for 12 weeks. The primary efficacy evaluation was the change from baseline to week 4 in 7-day mean composite score from the GCSI- 24H (a daily version of the GCSI including 3 subscales—nausea/vomiting, postprandial fullness/early satiety, and bloating) for each treatment arm compared with placebo. Day 28 gastric emptying was assessed using gastric emptying scintigraphy (GES). Results: In total, 232 patients were randomized; 59 to placebo, 59 to VEL 5 mg, 56 to VEL 15 mg, and 58 to VEL 30 mg. The population was 79% female, 88% White, and 51% diabetic (mean HbA1C 7.3%), with a mean (standard deviation) age of 50 (13.5) years and baseline mean GCSI score of 3.1 points. Symptom improvement showed a reverse dose response. The least-squares mean ± standard error change in GCSI-24H total score from baseline to week 4 for patients taking VEL 5, 15, and 30 mg was -1.5 ± 0.13, -1.2 ± 0.14, and -1.0 ± 0.13, respectively, vs -1.1 ± 0.13 for those taking placebo; the treatment difference relative to placebo was statistically significant only for VEL 5 mg (-0.4 ± 0.18, nominal p = 0.0327). Treatment with VEL 5 mg resulted in numerical improvements in all symptom domains. Changes from baseline were similar in patients with idiopathic vs diabetic gastroparesis, but a large placebo effect resulted in a smaller treatment effect in patients with diabetes (Figure 1). At week 12, VEL 5 mg numerically reduced GCSI-24H total score compared with placebo (treatment difference [95% confidence interval], -0.3 [-0.73, 0.10]; nominal p = 0.1331). Normalization of gastric emptying (<10% reduction in GES hour 4 retention) occurred in 44%, 65%, and 71% of patients taking VEL 5, 15, and 30 mg, respectively, compared with 0% for those taking placebo (Figure 2). VEL was generally well tolerated. The most common adverse events (AEs) across all treatment groups were diarrhea, nausea, and headache. No hyperglycemia AEs were observed with VEL. Numbers of serious AEs were similar for VEL vs placebo. Conclusions: VEL treatment demonstrated a powerful prokinetic effect, reduced gastroparesis symptoms, and was generally well tolerated in patients with both diabetic and idiopathic gastroparesis, setting the stage for future phase 3 studies evaluating efficacy of VEL in patients with gastroparesis. Figure 1. Week 4 GCSI 24H Total Score. CI, confidence interval; DIFF, treatment difference; GCSI 24H, daily Gastroparesis Cardinal Symptom Index; PLA, placebo; VEL, velusetrag. S-164 AGA Abstracts Figure 2. LS Mean Change in GES Percentage Retention by Hour. GES, gastric emptying scintigraphy; LS, least-squares. 785 SEXUAL DIMORPHIC EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS Tijs Louwies, Beverley Greenwood-Van Meerveld Background: Symptoms of irritable bowel syndrome, including chronic abdominal pain, are more frequently reported in women with a history of early life stress (ELS). We have previously shown that unpredictable neonatal ELS leads to visceral hypersensitivity in female rats, with underlying increases in both glucocorticoid receptor and corticotropin releasing hormone gene expression in the central nucleus of the amygdala (CeA). Epigenetic mecha- nisms, such as aberrant histone acetylation, can maintain this long-term dysregulated gene expression. In this present study, we explored the hypothesis that histone acetyltransferase (HAT) inhibition in the CeA could ameliorate visceral hypersensitivity in adult rats previously exposed to neonatal unpredictable stress. Methods: Male and female neonatal rats (n= 7/ group) were exposed to unpredictable or predictable ELS from postnatal day (PND) 8 to 12. Odor only treated rats served as controls. In adulthood (PND 90), rats underwent stereotaxic implantation of an indwelling cannula for microinjections into the CeA. Garcinol, (1 μg/μl), a HAT inhibitor, or vehicle control was infused bilaterally into the CeA for 7 consecutive days. Twenty-four hours following the final infusion, colonic sensitivity was assessed in freely moving rats via visceromotor response (VMR) to graded pressures of isobaric colorectal distension (20, 40 and 60 mmHg) and quantified as the number of abdominal contractions during the distension period. The cannula placement into the CeA was confirmed with post-mortem histology. Apoptag was used to assess potential damage following the infusions in the CeA and any rats with abnormally increased apoptosis in the CeA were excluded from the study. A two-way ANOVA with Bonferroni post-hoc analysis was used to test statistical significance. Results: In female rats, neonatal unpredictable ELS induced colonic hypersensitivity compared to their control and male counterparts. Female rats that underwent unpredictable ELS showed 33±8 abdominal contractions at 60 mmHg compared to 15±3 (p<0.001) and 19±6 (p<0.01) in their respective female and male controls. After stereotaxic administration of the HAT inhibitor directly into the CeA, the number of abdominal contractions in females exposed to unpredictable ELS was reduced to 19±6 at 60 mmHg (p<0.0001). The HAT inhibitor administered directly into the CeA was without effect on colonic sensitivity in male and female controls. Summary: Inhibition of HATs in the CeA reversed visceral hypersensitivity after unpredictable ELS in females. Conclusion: Our data suggests that epigenetic dysregulation, specifically histone acetylation in the CeA, plays is an important mechanism for “memorizing” early life stressful events mediating visceral pain in adulthood. BGVM is the recipient of a Senior Research Career Scientist award from the Department of Veterans Affairs. 786 HOME BIOFEEDBACK THERAPY WITH NOVEL DEVICE VERSUS OFFICE BIOFEEDBACK THERAPY FOR FECAL INCONTINENCE: RANDOMIZED CONTROLLED STUDY Amol Sharma, Xuelian Xiang, Yun Yan, Tanisa Patcharatrakul, Rachael Parr, Anam Herekar, Deepak Nag Ayyala, Satish S. Rao Background: Biofeedback therapy (BT), an effective treatment for fecal incontinence (FI), is labor intensive, not widely available and may decline in efficacy over time. We hypothesized that home device-assisted BT (HBT) is as effective as office BT (OBT). Methods: Patients with FI (>1 episode/wk) were randomized to HBT, using a novel biofeedback device (InToneMV, InControl Medical, WI, USA) or OBT. The FDA-approved home device consists of an inflatable probe for resistance training, metal electrodes for both low and high frequency electrical stimulation, a hand-held monitor with timer and voice-guided instructions, and