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T1256 The Role of Quantitative Analysis (Strain Ratio) of Transrectal Endoscopic Ultrasound (TRUS) Elastography in Inflammatory Bowel Disease (IBD)
AGA Abstracts
12 months. The UMC group has routine care as directed by their physician and 6 and 12 month follow-up. Results: 311 eligible subjects were identified:156 allocated to UMC; 155 to +CBT. To date, 64 participants have been contacted (26 UMC [14male], 38 +CBT [16 male]), aged 18 to 82 years (M=38). 42 (66%) had Crohn's Disease (CD). Experimental group: Eight of 38 invited to +CBT, accepted (7 female), 15 declined (7 female) and 15 are still considering participation. The commonest reason for declining was work commitments, other reasons included travel and current lack of IBD symptoms. After psychological screening, 3/8 patients were considered unsuitable for group CBT: depression as a primary diagnosis requiring intervention, psychiatric co morbidity not amenable to CBT and patient already receiving psychological treatment (n=1 each). Control group: Ten of 26 participants invited to UMC accepted (8 male), 9 declined (3 male) and 7 are still considering participation. Reasons for declining included no IBD symptoms, moving interstate or involvement in other research studies. Summary: Preliminary data show a large unmet need for psychological support, with 38% of those accepting CBT having overt psychological problems. There is a clear gender preference for women to accept the CBT invitation whereas more men accept UMC (p<0.02). Practical considerations such as work, time and lack of ongoing symptoms are the main drivers of the low response rate. We will address this by developing a parallel CBT program for remote access to allow broader participation.
up to 3200 mg/day. Gastrointestinal adverse events (nausea, abdominal pain, diarrhoea) increased with dose, being generally mild and reversible. Doses of dersalazine sodium up to 2400 mg/day were selected and are currently being tested in Ulcerative Colitis patients in a phase IIa study. T1256 The Role of Quantitative Analysis (Strain Ratio) of Transrectal Endoscopic Ultrasound (TRUS) Elastography in Inflammatory Bowel Disease (IBD) Nadan Rustemovic, Silvija Cukovic-Cavka, Marko Brinar, Davor Radic, Milorad Opacic, Rajko Ostojic, Zeljko Krznaric, Roland Pulanic, Boris Vucelic BACKGROUND AND AIMS: Establishing the diagnosis of IBD is sometimes very difficult. When IBD is confined to the colon, there is a lack of diagnostic tools for distinction between Crohn's colitis and ulcerative colitis, which is especially important in the definitive phenotyping before surgery. The aim of this study was to assess the potential role of the TRUS elastography in distinction between MC and UC. The idea is based upon the fact that MC is transmural disease and UC is limited to the mucosa and submucosa. These tissue characteristics are reflected in differences of the elasticity in rectal and perirectal tissue. Changes in the tissue elasticity can be obtained qualitatively by elastography with different coloures (from red-soft tissue to blue-hard tissue) or quantitatively using strain ratio score or histograms. METHODS: Rectal wall thickness and elastomode of patients were measured by TRUS elastography. Endoscopist was blind for patient diagnosis. SPSS ver. 15 was used for statistical analysis. Strain ratio is ratio of strain between two regions of interest (ROI) in the same image. Mucosal tissue was used as first ROI and perirectal tissue as second. SR was measured 3 times and middle value was used in statistical analysis. RESULTS: In study we included 46 patients; 29 patients with MC and 17 patients with UC, and 28 non-IBD controls. There was a significant difference in rectal wall thickness between IBD group and controls (median 4,85 interquartile range (IQR) [3,85-6,05] vs median 3,6 IQR [3,1-4,4], p= 0,0001). There was a significant difference in rectal wall thickness betwen both CD patients (p=0,0001) and UC patients (p=0,04) and controls with both CD and UC patients having thicker rectal walls compared to controls. Interestingly CD patients without rectal involvment (n=17) had significantly thicker rectal wall compared to controls (p=0,017). The same was true for CD patients with rectal involment whose disease was in remission at the time of investigation (p=0,02). In CD patients there was a significant difference in strain ratio compared to controls (median 1,14 IQR [0,66-1,48]) vs (median 0,68 IQR [0,510,89]) with CD patients having higher strain ratio (p=0,0001). We then compared CD and UC patients and found that CD patients had significantly higher strain ratio compared to the UC group (median 1,14 IQR[0,66-1,48] vs median 0,5 IQR [0,32-0,77]; p=0,0001). No differences in age at diagnosis, age at TRUS, disease duration to TRUS and rectal wall thickness were found. CONCLUSION: TRUS elastography provides a valuable information regarding the stiffness of the rectal and perirectal tissue, and can help to differentiate MC from UC.
T1254 Efficacy of Once-Daily Versus Twice-Daily Mesalazine (Pentasa®): SubAnalysis of the Left-Sided Colitis Population in the Randomised PODIUM Trial Severine Vermeire, Ragnar Befrits, Bernd Bokemeyer, Ivo Gill, Daniel W. Hommes, Per Broberg, Axel U. Dignass AIM Ulcerative colitis (UC) is a chronic disease of the colon that is associated with periods of remission and relapse. Oral PENTASA, a 5-aminosalicylate (5-ASA) is the current standard of care for treatment of active UC [1,2], and once-daily (OD) 2g PENTASA sachet has previously been shown to demonstrate superior efficacy compared with twice-daily (BD) dosing [3]. The aim of this subpopulation analysis was to determine if PENTASA 2g OD versus 1g BD shows greater efficacy for maintenance of remission in patients with left-sided colitis, the most prevalent UC disease location [4]. MATERIALS AND METHODS The subanalysis was performed on data generated in the phase III PODIUM trial [3]. Patients with mild-to-moderate UC, currently in remission, who had experienced a relapse within the past year, were randomised to receive either PENTASA 2g OD or 1g BD. The primary endpoint for the study was a reduction in the UC Disease Activity Index (UCDAI). Criteria included rectal bleeding, stool frequency and physician global assessment and mucosal appearance. RESULTS Of the total population (362 patients) in the PODIUM trial, 72% had left-sided colitis and 28% had pancolitis. Kaplan-Meier analysis of remission at year one using UCDAI criteria in the overall population showed >70% of patients remained in remission (a difference of 12% in favour of OD dosing). These results are comparable to those in patients with left-sided colitis where remission rates at one year were 69% (95% confidence interval [CI]: 59.5-76.5) for PENTASA OD versus 61% (95% CI: 51.4-69.6) for BD. The CI of the difference (-4.8-20.2) lies above -10 (the non-inferiority margin used in the primary analysis), indicating non-inferiority of OD versus BD in patients with left-sided UC. Remission rates at end-of-study in patients with left-sided colitis were 71% (95% CI: 63.5-79.3) for PENTASA OD and 63% (95% CI: 54.9-71.9) for PENTASA BD. CONCLUSIONS These results show that patients with left-sided colitis demonstrate similar efficacy with PENTASA to those in the overall PODIUM trial population, indicating that there is sufficient availability of PENTASA in the distal colon. PENTASA 2g OD demonstrates higher compliance rates and increased efficacy than BD dosing in patients with left-sided colitis and is therefore the maintenance therapy for patients with mild-to-moderate UC, including those with left-sided colitis. REFERENCES 1. Moum B, et al. Scand J Gastrenterol 1997;32:1005-12. 2. Travis S, et al. J Crohn's Colitis 2008;2:24-62. 3. Dignass AU, et al. Clin Gastroenterol Hepatol 2009;7:762-9. 4. Niv Y, et al. Am J Gastroenterol 1987;82:1046-51.
T1257 Characterization of Changes of Serum Anti-Glycan Antibodies in Individual Patients Over Time in Inflammatory Bowel Disease (IBD) Florian Rieder, Stephan Schleder, Alexandra Wolf, Anja Schirbel, Andre Franke, Andrea Dirmeier, Florian Obermeier, Rocio Lopez, Gerhard Rogler, Nir Dotan, Frank Klebl BACKGROUND: Serum anti-glycan antibodies, including the novel anti-laminarin (AntiL) and anti-chitin (Anti-C), are promising tests for both diagnosis and prognosis of Crohn's disease (CD). Little information is available on changes of anti-glycan antibody levels over time in individual IBD patients, as well as potential determinants of this phenomenon. AIMS: To I) define the magnitude of changes of anti-glycan antibody levels in individual patients; II) assess association of clinical factors or NOD2-genotype with magnitude of changes; III) perform a longitudinal analysis following individual patients in clinical situations over time. METHODS: 859 serum samples of 253 IBD patients (207 CD, 46 ulcerative colitis (UC)) were tested for the presence of Anti-L, Anti-C, ACCA, ALCA, AMCA and gASCA glycan antibodies by ELISA (Glycominds, Lod, Israel) in a blinded fashion. All patients had at least two and up to eleven serum samples taken during the disease course. Information on NOD2 genotype and CD behavior was available for each serum sample. RESULTS: Median follow up time for CD was 17.4 months (P25, P75: 8.0, 31.6 months) and for UC was 10.9 months (P25, P75: 4.9, 21.0 months). During the study period the antibody status for each single marker (positive versus negative for a respective antibody) remained stable in at least 81.6% of the CD subjects. Interestingly we detected marked changes in the overall immune response (quartile sum score) and levels of individual markers over time. The magnitude of fluctuation over time in CD patients was not associated with age at diagnosis, the antibody titers at the initial sample procurement, disease location, CD behavior or NOD2 genotype. According to a longitudinal analysis in individual CD subjects the antibody levels remained unchanged despite alterations in disease activity or the first occurrence of complicated CD behavior (fistula or stricture) or CD-related surgery. The IgA based markers ACCA, Anti-L and Anti-C showed very mild level increases as a function of time since diagnosis. In UC patients neither significant level nor status changes were observed. CONCLUSIONS: Despite a widely stable antibody status in CD patients during the follow-up period, we found marked changes in antibody levels that were not associated with clinical or genetic parameters. The widely stable antibody status in CD patients suggests a value of these markers for differential diagnosis and prediction of disease courses independently of the time of determination during the disease course. Further analysis will attempt to understand, why a subgroup of CD patients shows fluctuations in the antibody levels.
T1255 Tolerability and Pharmacokinetics of Repeated Doses of Dersalazine Sodium in Healthy Volunteers Natalia Fernandez-Deamo, Anna Solans, Roser Vives, Caridad Pontes, Manuel Merlos Background: Dersalazine sodium is a novel compound for the treatment of inflammatory bowel disease that is the result of the link of a potent Platelet Activating Factor (PAF) antagonist UR-12715 with a 5-ASA molecule by an azo bond. Azoreduction of dersalazine sodium produces the release of active metabolites for the topical treatment of inflammation in the colon. Objective: To study the tolerability, safety and pharmacokinetics of repeated oral doses of dersalazine sodium in healthy volunteers, in order to define the maximum dose to be explored in clinical trials in Ulcerative Colitis patients. Methods: A doubleblinded, randomised and placebo controlled tolerability study of repeated doses of dersalazine sodium during 14 days in healthy humans was done in a Phase I unit to compare 1200, 1600, 2400 and 3200 mg/day of dersalazine sodium with mesalazine at a dose of 1600 mg/ day and placebo in a total of 48 volunteers. Ethics Committee and Competent Authority approvals were granted before study start, and all subjects consented in writing before study participation. Results: Forty-eight (48) subjects were studied in four successive groups of twelve subjects each, of which eight subjects received active drug dersalazine sodium, two subjects received placebo and two the active standard reference mesalazine or 14 days. Doses up to 3200 mg were well tolerated. No serious adverse events were reported in the study. Most reported adverse events were of gastrointestinal type (nausea, abdominal pain, diarrhoea) and increased with dose, and were generally mild; all recovered. Two subjects interrupted the study treatment in the second cohort due to mild increases in ALT up to x3 fold the upper limit of normality, which recovered uneventfully. One of such subjects had received placebo and the other one dersalazine sodium 1600 mg/day. No other adverse events required treatment interruption. Systemic exposure to dersalazine was low and similar for all dose groups. Exposure to UR-12715 increased with dose although was not proportional. Similarly, exposure to N-acetyl-5-ASA in terms of AUC increased with dose although was not proportional either. Conclusions: Dersalazine sodium was well tolerated at doses
AGA Abstracts
S-522
12 months. The UMC group has routine care as directed by their physician and 6 and 12 month follow-up. Results: 311 eligible subjects were identified:156 allocated to UMC; 155 to +CBT. To date, 64 participants have been contacted (26 UMC [14male], 38 +CBT [16 male]), aged 18 to 82 years (M=38). 42 (66%) had Crohn's Disease (CD). Experimental group: Eight of 38 invited to +CBT, accepted (7 female), 15 declined (7 female) and 15 are still considering participation. The commonest reason for declining was work commitments, other reasons included travel and current lack of IBD symptoms. After psychological screening, 3/8 patients were considered unsuitable for group CBT: depression as a primary diagnosis requiring intervention, psychiatric co morbidity not amenable to CBT and patient already receiving psychological treatment (n=1 each). Control group: Ten of 26 participants invited to UMC accepted (8 male), 9 declined (3 male) and 7 are still considering participation. Reasons for declining included no IBD symptoms, moving interstate or involvement in other research studies. Summary: Preliminary data show a large unmet need for psychological support, with 38% of those accepting CBT having overt psychological problems. There is a clear gender preference for women to accept the CBT invitation whereas more men accept UMC (p<0.02). Practical considerations such as work, time and lack of ongoing symptoms are the main drivers of the low response rate. We will address this by developing a parallel CBT program for remote access to allow broader participation.
up to 3200 mg/day. Gastrointestinal adverse events (nausea, abdominal pain, diarrhoea) increased with dose, being generally mild and reversible. Doses of dersalazine sodium up to 2400 mg/day were selected and are currently being tested in Ulcerative Colitis patients in a phase IIa study. T1256 The Role of Quantitative Analysis (Strain Ratio) of Transrectal Endoscopic Ultrasound (TRUS) Elastography in Inflammatory Bowel Disease (IBD) Nadan Rustemovic, Silvija Cukovic-Cavka, Marko Brinar, Davor Radic, Milorad Opacic, Rajko Ostojic, Zeljko Krznaric, Roland Pulanic, Boris Vucelic BACKGROUND AND AIMS: Establishing the diagnosis of IBD is sometimes very difficult. When IBD is confined to the colon, there is a lack of diagnostic tools for distinction between Crohn's colitis and ulcerative colitis, which is especially important in the definitive phenotyping before surgery. The aim of this study was to assess the potential role of the TRUS elastography in distinction between MC and UC. The idea is based upon the fact that MC is transmural disease and UC is limited to the mucosa and submucosa. These tissue characteristics are reflected in differences of the elasticity in rectal and perirectal tissue. Changes in the tissue elasticity can be obtained qualitatively by elastography with different coloures (from red-soft tissue to blue-hard tissue) or quantitatively using strain ratio score or histograms. METHODS: Rectal wall thickness and elastomode of patients were measured by TRUS elastography. Endoscopist was blind for patient diagnosis. SPSS ver. 15 was used for statistical analysis. Strain ratio is ratio of strain between two regions of interest (ROI) in the same image. Mucosal tissue was used as first ROI and perirectal tissue as second. SR was measured 3 times and middle value was used in statistical analysis. RESULTS: In study we included 46 patients; 29 patients with MC and 17 patients with UC, and 28 non-IBD controls. There was a significant difference in rectal wall thickness between IBD group and controls (median 4,85 interquartile range (IQR) [3,85-6,05] vs median 3,6 IQR [3,1-4,4], p= 0,0001). There was a significant difference in rectal wall thickness betwen both CD patients (p=0,0001) and UC patients (p=0,04) and controls with both CD and UC patients having thicker rectal walls compared to controls. Interestingly CD patients without rectal involvment (n=17) had significantly thicker rectal wall compared to controls (p=0,017). The same was true for CD patients with rectal involment whose disease was in remission at the time of investigation (p=0,02). In CD patients there was a significant difference in strain ratio compared to controls (median 1,14 IQR [0,66-1,48]) vs (median 0,68 IQR [0,510,89]) with CD patients having higher strain ratio (p=0,0001). We then compared CD and UC patients and found that CD patients had significantly higher strain ratio compared to the UC group (median 1,14 IQR[0,66-1,48] vs median 0,5 IQR [0,32-0,77]; p=0,0001). No differences in age at diagnosis, age at TRUS, disease duration to TRUS and rectal wall thickness were found. CONCLUSION: TRUS elastography provides a valuable information regarding the stiffness of the rectal and perirectal tissue, and can help to differentiate MC from UC.
T1254 Efficacy of Once-Daily Versus Twice-Daily Mesalazine (Pentasa®): SubAnalysis of the Left-Sided Colitis Population in the Randomised PODIUM Trial Severine Vermeire, Ragnar Befrits, Bernd Bokemeyer, Ivo Gill, Daniel W. Hommes, Per Broberg, Axel U. Dignass AIM Ulcerative colitis (UC) is a chronic disease of the colon that is associated with periods of remission and relapse. Oral PENTASA, a 5-aminosalicylate (5-ASA) is the current standard of care for treatment of active UC [1,2], and once-daily (OD) 2g PENTASA sachet has previously been shown to demonstrate superior efficacy compared with twice-daily (BD) dosing [3]. The aim of this subpopulation analysis was to determine if PENTASA 2g OD versus 1g BD shows greater efficacy for maintenance of remission in patients with left-sided colitis, the most prevalent UC disease location [4]. MATERIALS AND METHODS The subanalysis was performed on data generated in the phase III PODIUM trial [3]. Patients with mild-to-moderate UC, currently in remission, who had experienced a relapse within the past year, were randomised to receive either PENTASA 2g OD or 1g BD. The primary endpoint for the study was a reduction in the UC Disease Activity Index (UCDAI). Criteria included rectal bleeding, stool frequency and physician global assessment and mucosal appearance. RESULTS Of the total population (362 patients) in the PODIUM trial, 72% had left-sided colitis and 28% had pancolitis. Kaplan-Meier analysis of remission at year one using UCDAI criteria in the overall population showed >70% of patients remained in remission (a difference of 12% in favour of OD dosing). These results are comparable to those in patients with left-sided colitis where remission rates at one year were 69% (95% confidence interval [CI]: 59.5-76.5) for PENTASA OD versus 61% (95% CI: 51.4-69.6) for BD. The CI of the difference (-4.8-20.2) lies above -10 (the non-inferiority margin used in the primary analysis), indicating non-inferiority of OD versus BD in patients with left-sided UC. Remission rates at end-of-study in patients with left-sided colitis were 71% (95% CI: 63.5-79.3) for PENTASA OD and 63% (95% CI: 54.9-71.9) for PENTASA BD. CONCLUSIONS These results show that patients with left-sided colitis demonstrate similar efficacy with PENTASA to those in the overall PODIUM trial population, indicating that there is sufficient availability of PENTASA in the distal colon. PENTASA 2g OD demonstrates higher compliance rates and increased efficacy than BD dosing in patients with left-sided colitis and is therefore the maintenance therapy for patients with mild-to-moderate UC, including those with left-sided colitis. REFERENCES 1. Moum B, et al. Scand J Gastrenterol 1997;32:1005-12. 2. Travis S, et al. J Crohn's Colitis 2008;2:24-62. 3. Dignass AU, et al. Clin Gastroenterol Hepatol 2009;7:762-9. 4. Niv Y, et al. Am J Gastroenterol 1987;82:1046-51.
T1257 Characterization of Changes of Serum Anti-Glycan Antibodies in Individual Patients Over Time in Inflammatory Bowel Disease (IBD) Florian Rieder, Stephan Schleder, Alexandra Wolf, Anja Schirbel, Andre Franke, Andrea Dirmeier, Florian Obermeier, Rocio Lopez, Gerhard Rogler, Nir Dotan, Frank Klebl BACKGROUND: Serum anti-glycan antibodies, including the novel anti-laminarin (AntiL) and anti-chitin (Anti-C), are promising tests for both diagnosis and prognosis of Crohn's disease (CD). Little information is available on changes of anti-glycan antibody levels over time in individual IBD patients, as well as potential determinants of this phenomenon. AIMS: To I) define the magnitude of changes of anti-glycan antibody levels in individual patients; II) assess association of clinical factors or NOD2-genotype with magnitude of changes; III) perform a longitudinal analysis following individual patients in clinical situations over time. METHODS: 859 serum samples of 253 IBD patients (207 CD, 46 ulcerative colitis (UC)) were tested for the presence of Anti-L, Anti-C, ACCA, ALCA, AMCA and gASCA glycan antibodies by ELISA (Glycominds, Lod, Israel) in a blinded fashion. All patients had at least two and up to eleven serum samples taken during the disease course. Information on NOD2 genotype and CD behavior was available for each serum sample. RESULTS: Median follow up time for CD was 17.4 months (P25, P75: 8.0, 31.6 months) and for UC was 10.9 months (P25, P75: 4.9, 21.0 months). During the study period the antibody status for each single marker (positive versus negative for a respective antibody) remained stable in at least 81.6% of the CD subjects. Interestingly we detected marked changes in the overall immune response (quartile sum score) and levels of individual markers over time. The magnitude of fluctuation over time in CD patients was not associated with age at diagnosis, the antibody titers at the initial sample procurement, disease location, CD behavior or NOD2 genotype. According to a longitudinal analysis in individual CD subjects the antibody levels remained unchanged despite alterations in disease activity or the first occurrence of complicated CD behavior (fistula or stricture) or CD-related surgery. The IgA based markers ACCA, Anti-L and Anti-C showed very mild level increases as a function of time since diagnosis. In UC patients neither significant level nor status changes were observed. CONCLUSIONS: Despite a widely stable antibody status in CD patients during the follow-up period, we found marked changes in antibody levels that were not associated with clinical or genetic parameters. The widely stable antibody status in CD patients suggests a value of these markers for differential diagnosis and prediction of disease courses independently of the time of determination during the disease course. Further analysis will attempt to understand, why a subgroup of CD patients shows fluctuations in the antibody levels.
T1255 Tolerability and Pharmacokinetics of Repeated Doses of Dersalazine Sodium in Healthy Volunteers Natalia Fernandez-Deamo, Anna Solans, Roser Vives, Caridad Pontes, Manuel Merlos Background: Dersalazine sodium is a novel compound for the treatment of inflammatory bowel disease that is the result of the link of a potent Platelet Activating Factor (PAF) antagonist UR-12715 with a 5-ASA molecule by an azo bond. Azoreduction of dersalazine sodium produces the release of active metabolites for the topical treatment of inflammation in the colon. Objective: To study the tolerability, safety and pharmacokinetics of repeated oral doses of dersalazine sodium in healthy volunteers, in order to define the maximum dose to be explored in clinical trials in Ulcerative Colitis patients. Methods: A doubleblinded, randomised and placebo controlled tolerability study of repeated doses of dersalazine sodium during 14 days in healthy humans was done in a Phase I unit to compare 1200, 1600, 2400 and 3200 mg/day of dersalazine sodium with mesalazine at a dose of 1600 mg/ day and placebo in a total of 48 volunteers. Ethics Committee and Competent Authority approvals were granted before study start, and all subjects consented in writing before study participation. Results: Forty-eight (48) subjects were studied in four successive groups of twelve subjects each, of which eight subjects received active drug dersalazine sodium, two subjects received placebo and two the active standard reference mesalazine or 14 days. Doses up to 3200 mg were well tolerated. No serious adverse events were reported in the study. Most reported adverse events were of gastrointestinal type (nausea, abdominal pain, diarrhoea) and increased with dose, and were generally mild; all recovered. Two subjects interrupted the study treatment in the second cohort due to mild increases in ALT up to x3 fold the upper limit of normality, which recovered uneventfully. One of such subjects had received placebo and the other one dersalazine sodium 1600 mg/day. No other adverse events required treatment interruption. Systemic exposure to dersalazine was low and similar for all dose groups. Exposure to UR-12715 increased with dose although was not proportional. Similarly, exposure to N-acetyl-5-ASA in terms of AUC increased with dose although was not proportional either. Conclusions: Dersalazine sodium was well tolerated at doses
AGA Abstracts
S-522