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953 Safety and Efficacy of Oral Budesonide Suspension for Maintenance Therapy in Eosinophilic Esophagitis: Results From a Prospective Open-Label Study of Adolescents and Adults
AGA Abstracts
had single/multiple colorectal adenomas resected by endoscopy were enrolled in the study. The patients were randomly assigned to receive metformin (250 mg daily) or placebo by a stratified randomisation method. After 1 year of administration of metformin or placebo, colonoscopies were performed to evaluate the adenoma/polyp incidence and the number of adenoma/polyp as primary endpoint. Our analysis included all the participants who underwent random allocation according to the intention-to-treat principle. This trial is registered with UMIN000006254. Results: Between September 2011, and December 2014, 498 subjects who had had single/multiple colorectal adenomas resected by endoscopy were enrolled in the study. 151 patients were randomly allocated; 79 were assigned to the metformin group and 72 were assigned to the placebo group. The incidences of total polyps and of adenomas in the metformin group was significantly lower than those in the placebo group: total polyps - metformin group 27/71, 38.0%, placebo group 35/62, 56.5%, p = 0.034, risk ratio 0.674 (95% CI 0.466-0.974); adenomas - metformin group 22/72, 30.6%, placebo group 32/62, p = 0.016, risk ratio 0.600 (95% CI 0.393-0.916). In the metformin group, the numbers of total polyps and adenomas were significantly lower than those in the placebo group (total polyps, p = 0.041; adenomas, p = 0.037). In the metformin group, the mean HOMA-IR value in non-recurrent patients after the 1-year treatment was significantly lower than the mean baseline value ( p = 0.029). In the placebo group, the mean baseline value of the HOMA-IR among recurrent patients was significantly higher than that in non-recurrent patients (p = 0.034). We observed no serious adverse events. Conclusion: The administration of low-dose metformin for 1 year to non-diabetic subjects was safe. Low-dose metformin reduced the incidence of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of CRC. The HOMAIR may act as a suitable predictor of responders to metformin in chemoprevention for CRC. However, further large-sample, long-term trials are needed to provide definitive conclusions.
eosinophil count (PEC) was 119 at OLE baseline and 29 at Week 24 (p<0.001); 49% achieved and maintained histologic response; EREFS scores decreased from 7.6 to 3.6 (p<0.001). For OBS/OBS, PEC was 38 at baseline and 72 post-treatment (p=0.007); 23% had ongoing histologic response; EREFS scores were unchanged (3.8 to 4.1; p=0.66). However, after stratified analysis, 42% of OBS/OBS patients with an initial histologic response maintained that response (PEC from 0.7 to 1.1; EREFS from 2.4 to 1.9); those without a response did not (PEC 66 to 94; EREFS from 4.8 to 4.9) (Fig 2). Results were similar after accounting for dose changes. AEs were uncommon, and cortisol levels or growth velocity (for age <18 years) did not change in either group. Four patients in placebo/OBS had esophageal candidiasis. Conclusions: In the largest prospective cohort of EoE patients treated with topical steroids to date, OBS was effective in maintaining endoscopic and histologic remission for up to 24 weeks, and no unexpected safety signals were noted. In histologic non-responders, a longer duration of topical steroids did not lead to improved response. Written on behalf of the MPI-101-06 Investigators
952 Active Gastric Inflammation in Human Volunteers After Exposure to a CagPositive H. pylori Challenge in a Placebo Controlled Vaccine Trial Peter Malfertheiner, Michael Selgrad, Thomas Wex, Albert Roessner, David Y. Graham, Giuseppe del Giudice Background and Aim: Following an oral challenge with a Cag-positive H. pylori strain approximately half of the subjects became H. pylori negative at the end of a placebo controlled vaccine trial. The persistence of residual active gastric inflammation in spite of no detectable H. pylori in these individuals prompted us to follow them up. Patients and Methods: A total of 35 subjects were included in this follow up study. 18 subjects in the vaccine trial were challenged orally with H. pylori and tested negative in all diagnostic tests, including histology, culture, 13C-UBT and fecal antigen test (FAT) (3 months after the challenge). However they showed persistent chronic active inflammation and were not treated with antibiotics (group 1), 17 subjects who received parenteral H. pylori vaccine were not exposed to H. pylori challenge and served as controls (group 2). 17 from group 1 and all 17 from group 2 underwent esophago-gastro-duodenoscopy (EGD) at least 12 months after their last visit in connection with the trial. Gastric biopsies were taken for histology (updated Sydney classification), H. pylori culture and rapid urease test. Non invasive testing included 13C-UBT, fecal antigen test and H. pylori serology. Results: 12 months after the end of the trial 7 (39%) of group 1 no longer had gastric mucosal inflammation. In 10 (55%) chronic active gastritis persisted and was scored mild in 6,moderate in 2 and severe in 2. H. pylori was detected by UBT and FAT in 2. All subjects with chronic active gastritis independently of their H. pylori status received H. pylori eradication therapy and at EGD follow up 6 to 10 weeks later in 7 no or minimal active inflammation was detected. 2 subjects had moderate active gastric inflammation and also in these at further EGD followup 6 months later active gastric inflammation had completely resolved. 1 subject of group 1 did not undergo EGD because of pregnancy but she was H. pylori negative in all non invasive tests. None of the 17 subjects in group 2 had any gastric mucosal inflammation. Conclusion: There are several lessons to be learned from this study and they include: a) after H. pylori challenge the presence of continuing chronic active gastritis suggests inapparent infection and should promptly receive retreatment. b) recrudescence of H. pylori infection may occur with significant delay in some subjects despite apparent cure according to the results of a complete set of negative diagnostic H. pylori tests.
Figure 1
Figure 2
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954
Safety and Efficacy of Oral Budesonide Suspension for Maintenance Therapy in Eosinophilic Esophagitis: Results From a Prospective Open-Label Study of Adolescents and Adults Evan Dellon, David A. Katzka, Margaret H. Collins, Mohamed Hamdani, Sandeep K. Gupta, Ikuo Hirano
Proton-Pump Inhibitor (PPI) Versus Histamine-2 Receptor Antagonist (H2RA) for the Prevention of Recurrent Non-Variceal Upper Gastrointestinal Bleeding in High-Risk Users of Low-Dose Aspirin (ASA) Francis K. Chan, Moe H. Kyaw, Pui K. Cheong, Jessica Ching, Yee Kit Tse, Long Yan K. Lam, Siew C. Ng, Tetsuya Tanigawa, Tetsuo Arakawa
Background: Eosinophilic esophagitis (EoE) is a chronic disease and maintenance therapy is needed for most patients. While topical corticosteroids are the first line pharmacologic treatment, data regarding long-term safety and efficacy are limited. Aim: To determine if oral budesonide suspension (OBS), a muco-adherent topical steroid formulation, is safe and effective for inducing and maintaining histologic response and improving endoscopic severity in adolescents and adults with EoE. Methods: We conducted an open-label extension (OLE) of a multicenter, randomized, double-blind, placebo-controlled trial (NCT01642212) from 10/2012 to 9/2014. Participants aged 11-40 years with EoE diagnosed per 2011 consensus guidelines, who completed the RCT treatment period (12 wks of OBS 2 mg bid or placebo), and who had post-treatment esophageal biopsies could receive 24 additional weeks of openlabel OBS. During the first 12 weeks of OLE, all patients were given OBS 2 mg once daily, regardless of prior allocation. Thereafter, dose increases to 1.5 mg bid and 2 mg bid were allowed as clinically indicated. Outcomes were histologic response ( £6 eos/hpf) and endoscopic severity (EREFS score; range 0-20) after 24 weeks. Safety parameters were also assessed. Esophageal biopsies were read centrally by a single pathologist blinded to allocation. Analysis was stratified by those who first received placebo and then OBS ("placebo/OBS") and those who received OBS throughout ("OBS/OBS"), and by histologic response. Results: A total of 82 patients entered OLE, 37 in the placebo/OBS group and 45 in OBS/OBS; 27 (73%) and 37 (82%) completed the 24 week treatment (Fig 1). For placebo/OBS, peak
BACKROUND We have previously shown that co-treatment with a PPI to be effective for secondary prevention of ASA induced ulcer bleeding [Chan FK et al. NEJM 2005]. However, there remain concerns about potential drug interactions and other side effects with PPIs. H2RAs are commonly used gastroprotective agents but their efficacy in ASA users with high bleeding risk is unclear. We compared a PPI with a H2RA for prevention of recurrent nonvariceal upper gastrointestinal bleeding in users of ASA with a history of ulcer bleeding. METHODS This was a one-year, double blinded, randomized trial of a PPI versus a H2RA in ASA users with a history of endoscopically confirmed ulcer bleeding. After healing of ulcers, those who had negative tests for H. pylori resumed ASA 80 mg daily. They were randomly assigned to receive either 20mg of rabeprazole once daily or 40mg of famotidine once daily for up to 12 months. Endoscopy was repeated if they developed symptoms of recurrent ulcer bleeding, had a drop in (Hb) >2 g/dL, withdrew early due to severe dyspepsia, or completed 12 months of follow-up.The primary endpoint was non-variceal upper gastrointestinal bleeding, which was defined as hematemesis, melena, or a decrease in the hemoglobin level of at least 2.0 g per deciliter with ulcers or bleeding lesions as adjudicated by an independent committee. Secondary endpoints included: 1) a composite endpoint of recurrent non-variceal upper gastrointestinal bleeding, endoscopic ulcers and early withdrawal due to severe dyspespia; 2) lower gastrointestinal bleeding; and 3) cardiothrombotic events.
AGA Abstracts
S-188
had single/multiple colorectal adenomas resected by endoscopy were enrolled in the study. The patients were randomly assigned to receive metformin (250 mg daily) or placebo by a stratified randomisation method. After 1 year of administration of metformin or placebo, colonoscopies were performed to evaluate the adenoma/polyp incidence and the number of adenoma/polyp as primary endpoint. Our analysis included all the participants who underwent random allocation according to the intention-to-treat principle. This trial is registered with UMIN000006254. Results: Between September 2011, and December 2014, 498 subjects who had had single/multiple colorectal adenomas resected by endoscopy were enrolled in the study. 151 patients were randomly allocated; 79 were assigned to the metformin group and 72 were assigned to the placebo group. The incidences of total polyps and of adenomas in the metformin group was significantly lower than those in the placebo group: total polyps - metformin group 27/71, 38.0%, placebo group 35/62, 56.5%, p = 0.034, risk ratio 0.674 (95% CI 0.466-0.974); adenomas - metformin group 22/72, 30.6%, placebo group 32/62, p = 0.016, risk ratio 0.600 (95% CI 0.393-0.916). In the metformin group, the numbers of total polyps and adenomas were significantly lower than those in the placebo group (total polyps, p = 0.041; adenomas, p = 0.037). In the metformin group, the mean HOMA-IR value in non-recurrent patients after the 1-year treatment was significantly lower than the mean baseline value ( p = 0.029). In the placebo group, the mean baseline value of the HOMA-IR among recurrent patients was significantly higher than that in non-recurrent patients (p = 0.034). We observed no serious adverse events. Conclusion: The administration of low-dose metformin for 1 year to non-diabetic subjects was safe. Low-dose metformin reduced the incidence of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of CRC. The HOMAIR may act as a suitable predictor of responders to metformin in chemoprevention for CRC. However, further large-sample, long-term trials are needed to provide definitive conclusions.
eosinophil count (PEC) was 119 at OLE baseline and 29 at Week 24 (p<0.001); 49% achieved and maintained histologic response; EREFS scores decreased from 7.6 to 3.6 (p<0.001). For OBS/OBS, PEC was 38 at baseline and 72 post-treatment (p=0.007); 23% had ongoing histologic response; EREFS scores were unchanged (3.8 to 4.1; p=0.66). However, after stratified analysis, 42% of OBS/OBS patients with an initial histologic response maintained that response (PEC from 0.7 to 1.1; EREFS from 2.4 to 1.9); those without a response did not (PEC 66 to 94; EREFS from 4.8 to 4.9) (Fig 2). Results were similar after accounting for dose changes. AEs were uncommon, and cortisol levels or growth velocity (for age <18 years) did not change in either group. Four patients in placebo/OBS had esophageal candidiasis. Conclusions: In the largest prospective cohort of EoE patients treated with topical steroids to date, OBS was effective in maintaining endoscopic and histologic remission for up to 24 weeks, and no unexpected safety signals were noted. In histologic non-responders, a longer duration of topical steroids did not lead to improved response. Written on behalf of the MPI-101-06 Investigators
952 Active Gastric Inflammation in Human Volunteers After Exposure to a CagPositive H. pylori Challenge in a Placebo Controlled Vaccine Trial Peter Malfertheiner, Michael Selgrad, Thomas Wex, Albert Roessner, David Y. Graham, Giuseppe del Giudice Background and Aim: Following an oral challenge with a Cag-positive H. pylori strain approximately half of the subjects became H. pylori negative at the end of a placebo controlled vaccine trial. The persistence of residual active gastric inflammation in spite of no detectable H. pylori in these individuals prompted us to follow them up. Patients and Methods: A total of 35 subjects were included in this follow up study. 18 subjects in the vaccine trial were challenged orally with H. pylori and tested negative in all diagnostic tests, including histology, culture, 13C-UBT and fecal antigen test (FAT) (3 months after the challenge). However they showed persistent chronic active inflammation and were not treated with antibiotics (group 1), 17 subjects who received parenteral H. pylori vaccine were not exposed to H. pylori challenge and served as controls (group 2). 17 from group 1 and all 17 from group 2 underwent esophago-gastro-duodenoscopy (EGD) at least 12 months after their last visit in connection with the trial. Gastric biopsies were taken for histology (updated Sydney classification), H. pylori culture and rapid urease test. Non invasive testing included 13C-UBT, fecal antigen test and H. pylori serology. Results: 12 months after the end of the trial 7 (39%) of group 1 no longer had gastric mucosal inflammation. In 10 (55%) chronic active gastritis persisted and was scored mild in 6,moderate in 2 and severe in 2. H. pylori was detected by UBT and FAT in 2. All subjects with chronic active gastritis independently of their H. pylori status received H. pylori eradication therapy and at EGD follow up 6 to 10 weeks later in 7 no or minimal active inflammation was detected. 2 subjects had moderate active gastric inflammation and also in these at further EGD followup 6 months later active gastric inflammation had completely resolved. 1 subject of group 1 did not undergo EGD because of pregnancy but she was H. pylori negative in all non invasive tests. None of the 17 subjects in group 2 had any gastric mucosal inflammation. Conclusion: There are several lessons to be learned from this study and they include: a) after H. pylori challenge the presence of continuing chronic active gastritis suggests inapparent infection and should promptly receive retreatment. b) recrudescence of H. pylori infection may occur with significant delay in some subjects despite apparent cure according to the results of a complete set of negative diagnostic H. pylori tests.
Figure 1
Figure 2
953
954
Safety and Efficacy of Oral Budesonide Suspension for Maintenance Therapy in Eosinophilic Esophagitis: Results From a Prospective Open-Label Study of Adolescents and Adults Evan Dellon, David A. Katzka, Margaret H. Collins, Mohamed Hamdani, Sandeep K. Gupta, Ikuo Hirano
Proton-Pump Inhibitor (PPI) Versus Histamine-2 Receptor Antagonist (H2RA) for the Prevention of Recurrent Non-Variceal Upper Gastrointestinal Bleeding in High-Risk Users of Low-Dose Aspirin (ASA) Francis K. Chan, Moe H. Kyaw, Pui K. Cheong, Jessica Ching, Yee Kit Tse, Long Yan K. Lam, Siew C. Ng, Tetsuya Tanigawa, Tetsuo Arakawa
Background: Eosinophilic esophagitis (EoE) is a chronic disease and maintenance therapy is needed for most patients. While topical corticosteroids are the first line pharmacologic treatment, data regarding long-term safety and efficacy are limited. Aim: To determine if oral budesonide suspension (OBS), a muco-adherent topical steroid formulation, is safe and effective for inducing and maintaining histologic response and improving endoscopic severity in adolescents and adults with EoE. Methods: We conducted an open-label extension (OLE) of a multicenter, randomized, double-blind, placebo-controlled trial (NCT01642212) from 10/2012 to 9/2014. Participants aged 11-40 years with EoE diagnosed per 2011 consensus guidelines, who completed the RCT treatment period (12 wks of OBS 2 mg bid or placebo), and who had post-treatment esophageal biopsies could receive 24 additional weeks of openlabel OBS. During the first 12 weeks of OLE, all patients were given OBS 2 mg once daily, regardless of prior allocation. Thereafter, dose increases to 1.5 mg bid and 2 mg bid were allowed as clinically indicated. Outcomes were histologic response ( £6 eos/hpf) and endoscopic severity (EREFS score; range 0-20) after 24 weeks. Safety parameters were also assessed. Esophageal biopsies were read centrally by a single pathologist blinded to allocation. Analysis was stratified by those who first received placebo and then OBS ("placebo/OBS") and those who received OBS throughout ("OBS/OBS"), and by histologic response. Results: A total of 82 patients entered OLE, 37 in the placebo/OBS group and 45 in OBS/OBS; 27 (73%) and 37 (82%) completed the 24 week treatment (Fig 1). For placebo/OBS, peak
BACKROUND We have previously shown that co-treatment with a PPI to be effective for secondary prevention of ASA induced ulcer bleeding [Chan FK et al. NEJM 2005]. However, there remain concerns about potential drug interactions and other side effects with PPIs. H2RAs are commonly used gastroprotective agents but their efficacy in ASA users with high bleeding risk is unclear. We compared a PPI with a H2RA for prevention of recurrent nonvariceal upper gastrointestinal bleeding in users of ASA with a history of ulcer bleeding. METHODS This was a one-year, double blinded, randomized trial of a PPI versus a H2RA in ASA users with a history of endoscopically confirmed ulcer bleeding. After healing of ulcers, those who had negative tests for H. pylori resumed ASA 80 mg daily. They were randomly assigned to receive either 20mg of rabeprazole once daily or 40mg of famotidine once daily for up to 12 months. Endoscopy was repeated if they developed symptoms of recurrent ulcer bleeding, had a drop in (Hb) >2 g/dL, withdrew early due to severe dyspepsia, or completed 12 months of follow-up.The primary endpoint was non-variceal upper gastrointestinal bleeding, which was defined as hematemesis, melena, or a decrease in the hemoglobin level of at least 2.0 g per deciliter with ulcers or bleeding lesions as adjudicated by an independent committee. Secondary endpoints included: 1) a composite endpoint of recurrent non-variceal upper gastrointestinal bleeding, endoscopic ulcers and early withdrawal due to severe dyspespia; 2) lower gastrointestinal bleeding; and 3) cardiothrombotic events.
AGA Abstracts
S-188