IV) With Teduglutide

Sa1959

Mean plasma citrulline levels

AGA Abstracts

A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose, ParallelGroup Study to Assess the Effects of Teduglutide on Gastric Emptying in Healthy Subjects Jolene Berg, Eric Kim, Yongbin Li, Nader Youssef Objective: Teduglutide, a human recombinant analog of glucagon-like peptide (GLP)-2, is a novel therapy in development for short bowel syndrome. GLPs are derived from proglucagon and, therefore, may affect gastric emptying. Change in gastric emptying may alter drug bioavailability. Our primary objective was to assess the effect of teduglutide on gastric emptying in healthy subjects, as measured by acetaminophen pharmacokinetics, an accepted measure of gastric emptying kinetics. Secondary objectives included assessment of the effects of teduglutide on preprandial and postprandial insulin, glucagon, and glucose. Methods: This double-blind, single-center study randomized 36 healthy subjects (22 male, 14 female) to receive subcutaneous doses of teduglutide 4 mg or placebo (2:1 ratio; 23:13) once daily on days 1-10 in the morning. The dose was chosen based on 0.05mg/kg/day in healthy subjects up to 80 kg in body weight. Gastric emptying was assessed by measuring acetaminophen levels pre-dose and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 3.5, 4, 5, 6, 8, 10, 12, and 14 hours after administration of 1000 mg acetaminophen on days 0 and 10. Blood levels of glucagon, insulin, and glucose were obtained at screening, day 0, and day 10. Results: No significant differences in gastric emptying (acetaminophen area under the concentration vs time curve from time 0 to the last measureable concentration [AUC0-last], AUC0-∞, maximum concentration [Cmax]) were observed on day 10 in subjects receiving teduglutide 4 mg vs subjects receiving placebo. There was no significant difference in time to acetaminophen Cmax between the 2 groups. Similarly, there were no significant differences in preprandial or postprandial insulin level parameters (AUC0-last, AUC0-inf, Cmax, AUC0-3h, Cmax03h) between the teduglutide and placebo groups. Teduglutide increased both fasting and postprandial glucagon levels (Figure), although the differences were small and not considered clinically meaningful. Teduglutide also increased postprandial glucose up to 10 hours compared with placebo (Figure). These changes were not considered clinically meaningful (<10% increase). Conclusions: Teduglutide does not affect gastric emptying in healthy subjects as measured by acetaminophen pharmacokinetics. In healthy subjects, teduglutide did not exert any clinically meaningful effects on serum insulin, glucagon, or glucose in either the fasted or fed state.

*n=27 for citrulline assessment. Sa1962 Short Bowel Syndrome Patients With Intestinal Failure (SBS-IF) Successfully Achieved Complete Independence From Parenteral Nutrition and/or Intravenous Fluid (PN/IV) With Teduglutide Palle B. Jeppesen, Stephen J. O'Keefe, Henry Chu, Bo Joelsson Background: Teduglutide (TED), a human recombinant analog of GLP-2, is a novel therapy in development for SBS-IF. It promotes expansion of remaining intestinal epithelium by increasing villus height and crypt depth. In the placebo-controlled phase III trials, significantly more TED-treated patients achieved a clinically meaningful response with 20−100% reduction in PN/IV. Among these patients, a subset achieved complete weaning from PN/IV. Objective: To describe the baseline characteristics of the 7 patients who were successfully weaned from PN/IV with TED. Methods: Two 24-week double-blind, randomized, parallel-group, placebocontrolled phase III trials assessed the efficacy and safety of TED in SBS-IF patients. The first trial compared daily subcutaneous injections of TED (0.05 or 0.10 mg/kg/d) vs placebo, while the second trial compared TED 0.05 mg/kg/d vs placebo. Each trial had an openlabel extension protocol that allowed for patients who received TED (TED/TED) or placebo (placebo/TED) during the initial study period to receive TED for an additional ≥28 weeks. The extension phase for the second trial is ongoing. Results: Combining all 173 patients who have received TED treatment in the 2 phase III trials, a total of 7 patients were weaned from PN/IV during the study period. Baseline demographics and disease characteristics were highly variable with wide ranging ages, remnant bowel lengths, and baseline PN/IV requirements. Also, there was no observable pattern of colon continuity or years of PN/IV dependence. These patients were weaned from PN/IV as early as 12 weeks and as late as 52 weeks after initiation of TED, suggesting long term use is associated with continued improvement in PN/IV weaning. The adverse event (AE) profile was similar to that of the overall study population, with gastrointestinal AEs being the most frequently reported (diarrhea, nausea, vomiting, abdominal distension). The 4 patients from the first trial remained off PN/IV as of end of the extension study and the 3 patients from the second trial remained off PN/IV in the extension study as of data cutoff on June 30, 2011. Conclusion: Despite expectations that ‘weaning' would be most common in patients with mild intestinal failure, our experience to date is that it occurs in a heterogeneous mix of SBS-IF patients.

Sa1961 Teduglutide, a Human Recombinant Analog of Glucagon-Like Peptide-2 (GLP2), Increases Plasma Citrulline Levels in Patients With Short Bowel Syndrome Bernard Messing, Francisca Joly, Lauren K. Schwartz, Kishore R. Iyer, Henry Chu, Nader Youssef Background: Teduglutide, a human recombinant analog of glucagon-like peptide-2 (GLP2), is a novel therapy in development for short bowel syndrome. Investigations of teduglutide in patients with short bowel syndrome have demonstrated significantly increased villus height and crypt depth in the small bowel mucosa. A proposed mechanism of action for teduglutide includes expansion of normal intestinal epithelium, with the resulting increased absorptive area providing a therapeutic advantage in short bowel syndrome. Plasma citrulline, an amino acid produced by enterocytes, has been considered a putative measure of remnant enterocyte mass in patients with short bowel syndrome (Crenn 2000). Objectives: The primary objective of this analysis was to assess changes in plasma citrulline at week 24 from baseline in short bowel syndrome patients included in 2 phase III clinical studies (CL0600004 and CL0600-020) of teduglutide. Methods: Both CL0600-004 and CL0600-020 were 24-week, double-blind, randomized, parallel group, placebo-controlled phase III studies in patients with short bowel syndrome. Here we report results from patients who received teduglutide 0.05 mg/kg/d or placebo. Plasma citrulline levels were analyzed and validated by the liquid chromatography tandem mass spectrometry (lc-ms) quantitative assay in all patients to assess potential effects on enterocyte mass. Results: In both the CL0600-004 and CL0600-020 studies, mean plasma citrulline increase at week 24 versus baseline was significantly greater in the teduglutide group compared with the placebo group [teduglutide 10.9 μmol/L vs. placebo 2.0 μmol/L (p<0.0001) and teduglutide 20.6 μmol/L vs. placebo 0.7 μmol/L (p<0.001), respectively]. At week 24, mean absolute citrulline levels among teduglutide treated patients reached 29.6 μmol/L and 37.9 μmol/L, respectively in the 2 studies. Conclusions: In 2 placebo-controlled phase III studies, patients treated with teduglutide 0.05 mg/kg/d had a significant increase in plasma citrulline at week 24, while patients in the placebo group had minimal change.

S-369

AGA Abstracts

Sa1970 Prevalence of Upper Gastrointestinal Tract Inflammation in Pediatric Patients With Newly Diagnosed Ulcerative Colitis Elaine Barfield, Vesta Salehi, Robbyn E. Sockolow, Debra Beneck, Aliza B. Solomon

AGA Abstracts

Background: Ulcerative colitis (UC) diffusely affects the colonic mucosa in a retrograde fashion from the rectum. Classic teaching emphasizes that UC spares the upper gastrointestinal (UGI) tract and, in fact, its distribution aids distinction from Crohn's disease (CD) particularly among pediatric patients. Some authors have reported rare UC patients to have UGI involvement although the frequency and severity with which this occurs is not known. The aim of this study was to determine the prevalence of UGI inflammation among newly diagnosed UC patients. We chose to evaluate pediatric patients because they often undergo routine endoscopic examination of the UGI tract during evaluation for colitic symptoms prior to initiation of therapy. Design: We identified 73 pediatric subjects with newly diagnosed IBD all of whom underwent endoscopy and biopsy of the UGI tract and colon prior to initiation of therapy. Subjects with hard criteria for CD (granulomas, chronic ileitis, strictures anal disease) were excluded from the study as were those with confounding inflammatory conditions (e.g. H. pylori infection) yielding a final study group of 33 subjects with presumed UC. Endoscopic and mucosal biopsy findings were reviewed, and the presence, distribution, and severity of inflammation were recorded. Result: There were 15 males and 18 females in the study group (mean: 11.4 years). Colonoscopy revealed colitis in all subjects which, on biopsy analysis, proved to be mild, moderate or severe. Four subjects (12%) had endoscopic and histologic active duodenitis. Twenty (60%) subjects had chronic gastritis which was inactive in 15 (45%) subjects and active in 4 (12%) subjects. One subject had chronic inactive gastritis of the the antrum and chronic active gastritis of the body. Giemsa stains were negative for H. pylori in all cases. Five (15%) subjects had esophagitis, all five had distal esophageal inflammation and three of them also had proximal inflammation. Two (6%) had greater than 15 eosinophils per high powered field in the esophagus suggestive of a dual diagnosis of eosinophilic esophagitis. Conclusion: Pediatric patients with newonset UC frequently have UGI tract inflammation which does not correlate with severity of colonic disease. Most patients with this finding have a clinical course typical of UC, provided they do not have other features to suggest CD. Therefore, the presence of UGI tract inflammation by itself should not be an exclusion criterion for UC in the pediatric population. Sa1971 Celiac Disease and Inflammatory Bowel Disease in Children: Is There a Link? Wael El-Matary, Richard N. Fedorak, A. Senthilselvan, Donald Spady Background: Immune disorders may cluster together. Aim: The aim of this work was to examine any possible inflammatory bowel disease (IBD) activity-related variations in IgA anti-tissue transglutaminase (tTG) levels in children IBD. The prevalence of celiac disease in children with IBD was also examined. Methods: In a single-center hospital-based prospective cohort study, children with IBD were recruited consecutively between September 2007January 2010, screened in 2 different time points for celiac disease using anti-tTG IgA antibodies and scoped if positive. Pediatric Crohn's disease activity and ulcerative colitis activity indices (PCDAI & PUCAI) were calculated in each time. Age-matched controls were recruited from children without IBD. Results: 164 children (85 with Crohn's) were recruited consecutively in each arm. The mean age for patients was 14.1 (SD 2.95), range 3.6 to 17 .3 years, 96 boys. Mean duration of IBD was 3.12 years (SD 2.84), range 0.6-14.9 years. The interval between the first and the second time of assessment ranged between 0.2- 2.1 years. Multiple linear regression analysis showed no correlation between neither the difference nor the absolute values of PCDAI, PUCAI and anti-tTG IgA antibody levels at the first time or the second time point. The prevalence of celiac disease was similar among patients and controls (1/164 (0.06%) Conclusions: In children with IBD, changes in disease activity did not significantly affect serum levels of IgA anti-tTG antibodies. The prevalence of celiac disease appears to be similar between children with IBD and without IBD.

Sa1963 Long-Term Patient Survival Rates Can Be Achieved While Receiving Home Parenteral Nutrition for Intestinal Failure John Siepler, Reid A. Nishikawa, Thomas G. Diamantidis, Rod J. Okamoto Background Patients with intestinal failure(IF) often require long term home parenteral nutrition(HPN) to sustain their nutritional status. While effective, HPN is not without complications. The complications can be classified as metabolic, infectious or technical. While these complications are often easily managed, some may result in death. Five year patient survival rates while receiving HPN vary widely in studies ranging from 50-90%. In addition, Intestinal transplant is a treatment option for IF with a widely quoted 50% five year patient survival rate. Objective: We wanted to determine the patient survival rates following the administration of HPN from one home care program compared to intestinal transplantation for IF. Methods: All HPN patients from one home care provider who were on HPN for at least one year and no more than 10 years qualified. Data collected included patient demographics, duration of HPN, survival, presence of ileocecal valve(ICV) and small bowel length. Data were collected and are reported as number of patients who survived at one, 2-3, 4-5 and 6-10 years divided by the total number of patients in that range while receiving HPN. Statistical analysis was performed using the Student's T test, with p<0.05 being considered significant Results: There were 52 patients who met the entry criteria. Patient survival at one, three, five and 10 years on HPN can be seen in the table. The numbers of patients with an ICV and length of small bowel are also seen in the table. More of the patients who survived had an ICV (61.2% vs 33%, P<0.01). Survivors had a longer SB length (140+/-109 vs 56+/-52cm p<0.01). Discussion: We report patient survival while receiving HPN for IF ranges from 100% at one year to 94.2% at ten years. More survivors had an ICV and a longer SB length. Patient survival following intestinal transplantation for IF in the national registry are reported as 73%,61% and 55% at one, three and five years respectively (Pediatrics2010;125:550). We report with this data, patient survival while receiving HPN to be 100%, 93%, 92%, and 94% at one, three, five, and ten years respectively. While this cohort represents stable HPN patients, it demonstrates that excellent patient survival rates can be achieved while receiving HPN for IF. Survival in HPN patients

AGA Abstracts

Sa1972 Small Bowel Disease in Children and Adolescents With Inflammatory Bowel Disease is Associated With Deteriorating Vitamin D Status Lauren Goldberg, Mabel Yau, Vesta Salehi, Robbyn E. Sockolow, Mary J. Ward, Zoltan Antal Background: Vitamin D can be absorbed in the gut or synthesized endogenously in the skin in response to sunlight exposure. Previous studies showed that vitamin D deficiency is prevalent among pediatric patients with inflammatory bowel disease (IBD). Deficiency may be caused by decreased exposure to sunlight, decreased intake, and malabsorption. Objective: (1) To describe the prevalence of vitamin D deficiency in pediatric subjects with IBD (2) To determine if small bowel disease significantly affects vitamin D status. Methods: A retrospective chart review was conducted of patients aged 2 to 21 years with IBD followed at an academically affiliated pediatric gastroenterology clinic in an urban setting from 9/ 2007 to 9/2011. Subjects were classified as having Ulcerative Colitis (UC) and Crohn's Disease (CD) with or without small bowel disease (SBD) based on endoscopy, colonoscopy and small bowel imaging. Serial serum levels of 25-hydroxy-vitamin D (VitD25) were obtained within the same year for each subject. Vitamin D deficiency, insufficiency, and sufficiency were defined respectively as <20 nmol/L, 20-30 nmol/L and > 30 nmol/L. Change in vitamin D status was classified into 3 groups; stable or improved sufficient, stable insufficient or deficient, and worsening to insufficient or deficient. Results: Of the 76 children evaluated, 24 (31%) had UC and 52 (68%) had CD. Vitamin D insufficiency was highly prevalent in IBD with 80% in UC and 60% in CD. Subjects with CD associated with SBD had the poorest vitamin D status noted on serial VitD25 measurements with 67% having stable insufficient/ deficient or worsening vitamin D status. In contrast, subjects with UC or CD and no SBD were more likely to have stable or improving vitamin D status (p < .05). Rate of supplementation was similar among all groups. Change in vitamin D status was not correlated with season. Conclusions: There is high prevalence of Vitamin D insufficiency in children and

S-370