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861 Effect of the GABAB Receptor Agonist Azd9343 On Transient Lower Esophageal Sphincter Relaxations and Acid Reflux in Healthy Volunteers: A Phase I Trial
AGA Abstracts
860
862
On-Demand Versus Daily Proton Pump Inhibitor (PPI) for Maintenance Treatment of Gastroesophageal Reflux Disease (GERD): A Double Blind, Double Dummy, Randomized Placebo Controlled Trial and Cost-Effectiveness Analysis Justin Wu, Yawen Chan, Kelvin K. Tsoi, Vincent W. Wong, Larry Lai, Grace Wong, Dorothy K. Chow, Philip W. Chiu, Ka Fai Danny Siu, Joseph J. Sung, Francis K. L. Chan
Is the Response of GERD Patients to PPI Therapy Affected By the Presence of IBS-Like Symptoms? Hubert Monnikes, Hubert Doerfler, Holger Schmitt, Peter Berghoefer, Robert Heading Introduction: This question was addressed in a large international study using the validated, self-assessed questionnaire ReQuestTM, a multi-dimensional instrument to evaluate the broad spectrum of gastroesophageal reflux disease (GERD) symptoms. Methods: In this open study 1549 patients (PP) were recruited in 168 centers in 21 countries worldwide. Patients were included after a symptom-based diagnosis of GERD reflecting a real life setting in medical practice. The investigator was asked, if the patient might additionally suffer from symptoms caused by Irritable Bowel Syndrome. Subsequentely, all patients were endoscoped and treated with pantoprazole 40 mg o.d. for 8 weeks. Treatment response was daily assessed by ReQuestTM and was defined as the score of the ReQuestTM-GI being below the pre-defined GERD symptom threshold on the 3 days prior to the visit at Week 4 and 8. Results: At baseline, 37% of patients (n=566) had non-erosive reflux disease (NERD), 63% (n=972) had erosive reflux disease (ERD). Treatment response in GERD patients with IBS at 4 and 8 weeks (45.1 [38.3, 52.0], 63.1 [56.2, 69.6]) were lower than in patients without IBS symptoms (63.3 [60.5, 66.0], 74.1 [71.6, 76.6]). Pre-post differences at both time points for acid-related symptoms were comparable between ERD and NERD patients with and without IBS symptoms (data not shown). Conclusion: IBS symptoms are significantly more frequent in NERD than ERD patients, and symptom burden is more severe in NERD with IBS than in ERD with IBS. GERD patients with IBS symptoms show a lower treatment response. Improvement of acid-related symptoms is similar in ERD and NERD irrespective of presence of IBS symptoms. Lower abdominal symptoms improve with treatment in both ERD and NERD patients. IBS positive NERD patients had the highest lower abdominal symptom score at baseline and showed the biggest improvement. Table 1: Treatment Response (ReQuest™-GI) and IBS Status in NERD and ERD Patients
Background: On-demand PPI has been shown to be an effective step-down therapy for GERD. But data on comparison with regular PPI is lacking. Aim: To compare the efficacy, quality of life (QoL) and cost-effectiveness of on-demand and daily PPI regimens in long-term management of mild GERD. Methods: Consecutive patients with weekly reflux symptoms for >6 months were prospectively recruited for assessment of reflux symptom score (0-3) and validated disease-specific GERD-QOL questionnaire (0-400). EGD defined esophagitis by LA classification. Exclusion criteria included NSAID use, peptic ulcer, esophagitis ≥ grade B, stricture or Barrett's esophagus. Eligible patients were given esomeprazole (Eso) 20 mg daily for 8 weeks as initial treatment. Patients with complete symptom resolution to Eso were randomized to (1) On-demand (OD) group: daily placebo + on-demand Eso 20 mg, or (2) Regular (R) group: daily Eso 20mg + on-demand placebo for 26 weeks. Treatment failure was defined as inadequate relief of reflux symptom by patient-reported global symptom assessment. Primary measure was treatment failure at 26 weeks. Results: 250 patients (Male= 87, Mean age: 51+/-11, NERD=205) were randomized (N=125 in each group). 37 (29.6%) patients in OD and 22 (17.6%) in R group had treatment failure at 26 weeks (p=0.025). The probability of treatment failure at 26 weeks was 31.6% (mean remission time: 21 weeks) for OD and 19.0% (mean remission time: 24 weeks) for R group, respectively (p=0.018, log rank). Among OD patients without treatment failure, PPI was taken in 20.5% of time and there was no significant difference in symptom severity (Median symptom score: 1, p= 0.34) or GERD-specific QoL measures (OD: 210.8 +/- 91.4 Vs R: 196.0 +/- 101.1, p=0.43) at 26 weeks compared to R patients. The cost-effectiveness ratio was US$15,144 for OD group and US$59,289 for R group. The incremental cost to achieve an additional patient with adequate symptom relief by switching from OD group to R group was US$318,272. Conclusion: On-demand PPI regimen is inferior to daily PPI regimen for long-term management of mild GERD. However, on-demand PPI strategy is much more cost-effective.
Probability of treatment failure over 26 weeks
NERD vs. ERD: *p=0.0260, $p=0.0363, #p=0.0295, N=number of evaluable patients Table 2: Lower abdominal symptoms (ReQuest™-GI score) in relation to investigatorassessed presence of IBS symptoms
861 Effect of the GABAB Receptor Agonist Azd9343 On Transient Lower Esophageal Sphincter Relaxations and Acid Reflux in Healthy Volunteers: A Phase I Trial Guy E. Boeckxstaens, Hanneke Beaumont, Hans Rydholm, Magnus Ruth, Aaltje Lei, Anders Lehmann, André Smout INTRODUCTION: Transient relaxations of the lower esophageal sphincter (TLESRs) are considered the main mechanism underlying gastroesophageal reflux both in healthy subjects and patients with reflux disease and therefore represent an interesting target for treatment. Baclofen, a GABAB receptor agonist, reduces the number of TLESRs and reflux episodes, but is not suitable for clinical application due to its central side effects. Therefore, new substances devoid of these side effects are required. In the present study, the effect of AZD9343, a new selective GABAB receptor agonist, was studied on meal-induced TLESRs and its safety profile was evaluated. METHODS: Twenty-seven healthy male subjects (1947 yrs) were included in a placebo-controlled, randomized, two-centre phase I study. All subjects underwent esophageal manometry (10 channel water perfused sleeve assembly) and pH-metry during 3hrs after ingestion of a solid meal. One and a half hour before meal ingestion, a single oral dose of placebo, 60 and 320 mg AZD9343 or 40 mg baclofen was given on 4 separate days at least 7 days apart. TLESRs and acid reflux episodes were identified according to previously published criteria (Holloway et al., 1995). RESULTS: 25 of the 27 studies were complete and suitable for analysis. Somnolence was most commonly reported as side effect after 320 mg AZD9343 and baclofen. Reversible short-lasting parasthesiae of mild intensity were reported after intake of 60 and 320 mg AZD9343. The highest dose of AZD9343 and baclofen significantly reduced the number of TLESRs in the postprandial period with an average of 32% (95% CI: 15-44%) and 40% (95% CI: 26-51%) respectively. Acid reflux episodes were also significantly reduced by both doses of AZD9343 and baclofen compared to placebo. Like baclofen, both doses of AZD9343 increased mean LES pressure before meal intake compared to placebo. Finally, 320 mg AZD9343 and baclofen reduced the number of swallows as compared to placebo (mean reduction of 22 % (95% CI: 6-35%) and 35% (95% CI: 18-49%) whereas no effect was seen after 60 mg AZD9343. CONCLUSION: Like baclofen, the selective GABAB receptor agonist AZD9343 dose-dependently reduces the number of TLESRs and acid reflux episodes, increases basal LES pressure and reduces swallowing. These findings extend the concept that GABAB agonists are potent reflux inhibitors.
AGA Abstracts
863 Changes in Esophageal Histology Following Esomeprazole or Laparoscopic Anti-Reflux Surgery for the Management of Chronic Gastroesophageal Reflux Disease: the Lotus Trial Experience Roberto Fiocca, Stephen E. Attwood, Christian Ell, Jean Paul Galmiche, Jan G. Hatlebakk, Lars R. Lundell, Luca Mastracci, Tore Lind, Ola Junghard Introduction: Changes in esophageal histology following anti-reflux therapy have been reported in few studies and most of them referred to short-term medical treatments and/or considered only one or a few individual lesions. We report the baseline, 1- and 3-year histological findings from a randomized study comparing the efficacy of esomeprazole (ESO) and laparoscopic anti-reflux surgery (LARS): the proportion of patients who remained in remission after 3 years was 93% for ESO and 90% for LARS. Methods: LOTUS is an open, parallel-group, multicenter, randomized, controlled trial conducted in eleven European countries (ClinicalTrials.gov identifier: NCT00251927). Treatment comprised LARS or ESO 20mg once daily (that could be increased to 40mg daily if needed). Two biopsies each from distal esophagus (2 cm above the Z-line) and the Z-line were taken at baseline, 1 and 3 years. The following lesions were assessed: basal cell hyperplasia (BCH), papillary elongation (PE), intercellular space dilatations (ISD) and presence of intraepithelial eosinophils (EOS), neutrophils and necrosis/erosion. BCH, PE and ISD were scored (0=absent, 1=mild, 2= marked) and, due to the patchy distribution of the lesions, only the most severe change was reported. A combined mean score (CMS) including BCH+PE+ISD+EOS was developed to describe the overall severity of all the lesions (range 0 to 2). The Wilcoxon signed rank test and a one sample t-test were used to evaluate 1- and 3-year changes. Results: A total of 554 patients were randomized (ESO: n=266; LARS: n=288). All lesions were consistently more severe on Z-line biopsies than at 2 cm, both at baseline and during the follow up. All lesions improved from baseline to 1 and 3 years, although to a different extent. All improvements except one (EOS from baseline to 3 years in the LARS group) were statistically significant. The total CMS (2 cm+Z line) changed from 0.95 to 0.57 (1 year) and to 0.49 (3 years) in the ESO arm, and from 0.91 to 0.56 (1 year) and to 0.52 (3 years) in the LARS arm (p<0.001 for both arms at 1 and 3 years). No significant differences in total CMS were seen between the ESO and LARS groups at any time point. Conclusions: Over the first 3
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860
862
On-Demand Versus Daily Proton Pump Inhibitor (PPI) for Maintenance Treatment of Gastroesophageal Reflux Disease (GERD): A Double Blind, Double Dummy, Randomized Placebo Controlled Trial and Cost-Effectiveness Analysis Justin Wu, Yawen Chan, Kelvin K. Tsoi, Vincent W. Wong, Larry Lai, Grace Wong, Dorothy K. Chow, Philip W. Chiu, Ka Fai Danny Siu, Joseph J. Sung, Francis K. L. Chan
Is the Response of GERD Patients to PPI Therapy Affected By the Presence of IBS-Like Symptoms? Hubert Monnikes, Hubert Doerfler, Holger Schmitt, Peter Berghoefer, Robert Heading Introduction: This question was addressed in a large international study using the validated, self-assessed questionnaire ReQuestTM, a multi-dimensional instrument to evaluate the broad spectrum of gastroesophageal reflux disease (GERD) symptoms. Methods: In this open study 1549 patients (PP) were recruited in 168 centers in 21 countries worldwide. Patients were included after a symptom-based diagnosis of GERD reflecting a real life setting in medical practice. The investigator was asked, if the patient might additionally suffer from symptoms caused by Irritable Bowel Syndrome. Subsequentely, all patients were endoscoped and treated with pantoprazole 40 mg o.d. for 8 weeks. Treatment response was daily assessed by ReQuestTM and was defined as the score of the ReQuestTM-GI being below the pre-defined GERD symptom threshold on the 3 days prior to the visit at Week 4 and 8. Results: At baseline, 37% of patients (n=566) had non-erosive reflux disease (NERD), 63% (n=972) had erosive reflux disease (ERD). Treatment response in GERD patients with IBS at 4 and 8 weeks (45.1 [38.3, 52.0], 63.1 [56.2, 69.6]) were lower than in patients without IBS symptoms (63.3 [60.5, 66.0], 74.1 [71.6, 76.6]). Pre-post differences at both time points for acid-related symptoms were comparable between ERD and NERD patients with and without IBS symptoms (data not shown). Conclusion: IBS symptoms are significantly more frequent in NERD than ERD patients, and symptom burden is more severe in NERD with IBS than in ERD with IBS. GERD patients with IBS symptoms show a lower treatment response. Improvement of acid-related symptoms is similar in ERD and NERD irrespective of presence of IBS symptoms. Lower abdominal symptoms improve with treatment in both ERD and NERD patients. IBS positive NERD patients had the highest lower abdominal symptom score at baseline and showed the biggest improvement. Table 1: Treatment Response (ReQuest™-GI) and IBS Status in NERD and ERD Patients
Background: On-demand PPI has been shown to be an effective step-down therapy for GERD. But data on comparison with regular PPI is lacking. Aim: To compare the efficacy, quality of life (QoL) and cost-effectiveness of on-demand and daily PPI regimens in long-term management of mild GERD. Methods: Consecutive patients with weekly reflux symptoms for >6 months were prospectively recruited for assessment of reflux symptom score (0-3) and validated disease-specific GERD-QOL questionnaire (0-400). EGD defined esophagitis by LA classification. Exclusion criteria included NSAID use, peptic ulcer, esophagitis ≥ grade B, stricture or Barrett's esophagus. Eligible patients were given esomeprazole (Eso) 20 mg daily for 8 weeks as initial treatment. Patients with complete symptom resolution to Eso were randomized to (1) On-demand (OD) group: daily placebo + on-demand Eso 20 mg, or (2) Regular (R) group: daily Eso 20mg + on-demand placebo for 26 weeks. Treatment failure was defined as inadequate relief of reflux symptom by patient-reported global symptom assessment. Primary measure was treatment failure at 26 weeks. Results: 250 patients (Male= 87, Mean age: 51+/-11, NERD=205) were randomized (N=125 in each group). 37 (29.6%) patients in OD and 22 (17.6%) in R group had treatment failure at 26 weeks (p=0.025). The probability of treatment failure at 26 weeks was 31.6% (mean remission time: 21 weeks) for OD and 19.0% (mean remission time: 24 weeks) for R group, respectively (p=0.018, log rank). Among OD patients without treatment failure, PPI was taken in 20.5% of time and there was no significant difference in symptom severity (Median symptom score: 1, p= 0.34) or GERD-specific QoL measures (OD: 210.8 +/- 91.4 Vs R: 196.0 +/- 101.1, p=0.43) at 26 weeks compared to R patients. The cost-effectiveness ratio was US$15,144 for OD group and US$59,289 for R group. The incremental cost to achieve an additional patient with adequate symptom relief by switching from OD group to R group was US$318,272. Conclusion: On-demand PPI regimen is inferior to daily PPI regimen for long-term management of mild GERD. However, on-demand PPI strategy is much more cost-effective.
Probability of treatment failure over 26 weeks
NERD vs. ERD: *p=0.0260, $p=0.0363, #p=0.0295, N=number of evaluable patients Table 2: Lower abdominal symptoms (ReQuest™-GI score) in relation to investigatorassessed presence of IBS symptoms
861 Effect of the GABAB Receptor Agonist Azd9343 On Transient Lower Esophageal Sphincter Relaxations and Acid Reflux in Healthy Volunteers: A Phase I Trial Guy E. Boeckxstaens, Hanneke Beaumont, Hans Rydholm, Magnus Ruth, Aaltje Lei, Anders Lehmann, André Smout INTRODUCTION: Transient relaxations of the lower esophageal sphincter (TLESRs) are considered the main mechanism underlying gastroesophageal reflux both in healthy subjects and patients with reflux disease and therefore represent an interesting target for treatment. Baclofen, a GABAB receptor agonist, reduces the number of TLESRs and reflux episodes, but is not suitable for clinical application due to its central side effects. Therefore, new substances devoid of these side effects are required. In the present study, the effect of AZD9343, a new selective GABAB receptor agonist, was studied on meal-induced TLESRs and its safety profile was evaluated. METHODS: Twenty-seven healthy male subjects (1947 yrs) were included in a placebo-controlled, randomized, two-centre phase I study. All subjects underwent esophageal manometry (10 channel water perfused sleeve assembly) and pH-metry during 3hrs after ingestion of a solid meal. One and a half hour before meal ingestion, a single oral dose of placebo, 60 and 320 mg AZD9343 or 40 mg baclofen was given on 4 separate days at least 7 days apart. TLESRs and acid reflux episodes were identified according to previously published criteria (Holloway et al., 1995). RESULTS: 25 of the 27 studies were complete and suitable for analysis. Somnolence was most commonly reported as side effect after 320 mg AZD9343 and baclofen. Reversible short-lasting parasthesiae of mild intensity were reported after intake of 60 and 320 mg AZD9343. The highest dose of AZD9343 and baclofen significantly reduced the number of TLESRs in the postprandial period with an average of 32% (95% CI: 15-44%) and 40% (95% CI: 26-51%) respectively. Acid reflux episodes were also significantly reduced by both doses of AZD9343 and baclofen compared to placebo. Like baclofen, both doses of AZD9343 increased mean LES pressure before meal intake compared to placebo. Finally, 320 mg AZD9343 and baclofen reduced the number of swallows as compared to placebo (mean reduction of 22 % (95% CI: 6-35%) and 35% (95% CI: 18-49%) whereas no effect was seen after 60 mg AZD9343. CONCLUSION: Like baclofen, the selective GABAB receptor agonist AZD9343 dose-dependently reduces the number of TLESRs and acid reflux episodes, increases basal LES pressure and reduces swallowing. These findings extend the concept that GABAB agonists are potent reflux inhibitors.
AGA Abstracts
863 Changes in Esophageal Histology Following Esomeprazole or Laparoscopic Anti-Reflux Surgery for the Management of Chronic Gastroesophageal Reflux Disease: the Lotus Trial Experience Roberto Fiocca, Stephen E. Attwood, Christian Ell, Jean Paul Galmiche, Jan G. Hatlebakk, Lars R. Lundell, Luca Mastracci, Tore Lind, Ola Junghard Introduction: Changes in esophageal histology following anti-reflux therapy have been reported in few studies and most of them referred to short-term medical treatments and/or considered only one or a few individual lesions. We report the baseline, 1- and 3-year histological findings from a randomized study comparing the efficacy of esomeprazole (ESO) and laparoscopic anti-reflux surgery (LARS): the proportion of patients who remained in remission after 3 years was 93% for ESO and 90% for LARS. Methods: LOTUS is an open, parallel-group, multicenter, randomized, controlled trial conducted in eleven European countries (ClinicalTrials.gov identifier: NCT00251927). Treatment comprised LARS or ESO 20mg once daily (that could be increased to 40mg daily if needed). Two biopsies each from distal esophagus (2 cm above the Z-line) and the Z-line were taken at baseline, 1 and 3 years. The following lesions were assessed: basal cell hyperplasia (BCH), papillary elongation (PE), intercellular space dilatations (ISD) and presence of intraepithelial eosinophils (EOS), neutrophils and necrosis/erosion. BCH, PE and ISD were scored (0=absent, 1=mild, 2= marked) and, due to the patchy distribution of the lesions, only the most severe change was reported. A combined mean score (CMS) including BCH+PE+ISD+EOS was developed to describe the overall severity of all the lesions (range 0 to 2). The Wilcoxon signed rank test and a one sample t-test were used to evaluate 1- and 3-year changes. Results: A total of 554 patients were randomized (ESO: n=266; LARS: n=288). All lesions were consistently more severe on Z-line biopsies than at 2 cm, both at baseline and during the follow up. All lesions improved from baseline to 1 and 3 years, although to a different extent. All improvements except one (EOS from baseline to 3 years in the LARS group) were statistically significant. The total CMS (2 cm+Z line) changed from 0.95 to 0.57 (1 year) and to 0.49 (3 years) in the ESO arm, and from 0.91 to 0.56 (1 year) and to 0.52 (3 years) in the LARS arm (p<0.001 for both arms at 1 and 3 years). No significant differences in total CMS were seen between the ESO and LARS groups at any time point. Conclusions: Over the first 3
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