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W1089 Safety of Adalimumab in Global Clinical Trials of Patients with Crohn's Disease
Methods: All pts with CD participating in the pivotal randomized controlled clinical trials, open-label extensions, and Phase IIIb studies were evaluated for safety at regular intervals. Rates of adverse events (AEs) of interest to physicians prescribing anti-TNF therapy were assessed per 100-pt-years (100-PYs) of ADA exposure. Standardized mortality ratios were calculated using the World Health Organization 2003 age-and sex-matched US mortality data. Results: As of 15 April 2008, the ADA CD clinical trial safety database contained data for 3,160 pts, representing 3,401.9-PYs of ADA exposure. The table below compares AE rates observed in all clinical trials in CD as of the 15 April 2008 cutoff to those from the 15 April 2007 safety update. The AE rates reported in ADA CD clinical trials were comparable to those reported in the rheumatoid arthritis trials.1 The calculated standardized mortality ratio in ADA-treated pts with CD, 0.44 (95% confidence interval: 0.12, 1.12), is lower than the published rate of 1.52 (95% confidence interval: 1.32, 1.74) reported in a recent metaanalysis of pts with CD.2 Conclusions: The safety profile of ADA in the CD clinical trial program was similar to that reported previously and to safety reports of other TNF antagonists in CD populations. Rates of AEs were comparable to previous reports spanning more than 10 years of clinical observation. ADA was well-tolerated, and no new safety signals were identified. References 1. Canavan C, et al. Aliment Pharmacol Ther. 2007;25:861-70. 2. Burmester GR, et al. Arthritis Rheum. 2007;56(Suppl):S399. Rates of AEs of Interest
W1088 Autologous Bone Marrow Derived Mesenchymal Stem Cell Treatment in Patients Refractory Crohn's Disease Patients Marjolijn Duijvestein, Marthe H. Verwey, Herma H. Fidder, Gijs R. van den Brink, Helene Roelofs, Jaap Jan Zwaginga, Willem E. Fibbe, Daniel Hommes
*Including lymphoma and nonmelanoma skin cancer. †Excluding tuberculosis. E=events. W1090
Despite the improvements in Crohn's Disease (CD) management with introduction of antiTNF compounds, a proportion of patients suffer from a poor quality of life due to disease relapse, repeat surgery, extraintestinal manifestations and drug side-effects. Mesenchymal Stem Cells (MSCs) are pluripotent cells that have potent immunosuppressive effects on T and B cells In Vitro and in animal models of chronic inflammation. Promising results have been obtained in patients with steroid resistant, acute and severe graft versus host disease (GvHD), including GvHD of the gut. The objective of this study is to determine the safety and feasibility of autologous bone marrow derived MSC therapy in patients with refractory CD. Methods: 8 adult patients (6 females/2 males, median age 33,5 years) with refractory, moderate to severe CD with a Crohn's Disease Activity Index (CDAI) score of at least 220 underwent bone marrow aspiration (100 ml) under local anesthesia. Mononuclear cells were isolated by density gradient centrifugation and plated in culture medium containing 10% Fetal Calf Serum. MSCs were expanded in culture until passage 1-3. To date, five patients received 2 doses of 1-2 million cells/kg bodyweight, intravenously, 7 days apart. Primary outcomes were feasibility and safety of autologous MSC expansion and infusion. Secondary outcomes were changes in the CDAI score and Crohn's Disease Endoscopic Index of Severity Score (CDEIS). Results: MSC from CD patients showed the typical spindle-shaped morphology and similar growth potential and yield comparable to MSCs from healthy donors (n= 8). The initial median CDAI score in the first five patients treated was 334 (range 254-350). MSC infusion was successful and without side effects, with exception of a mild allergic reaction to the cryopreservant dimethyl sulfoxide (DMSO) in one patient. The first patient was a chronic severe steroid refractory patient on the waiting list for surgery. Although an initial drop of CDAI was seen, she was operated upon due to poor general condition and persistent rectal blood loss. The other four treated patients showed an average decrease in median CDAI score of 107 points 6 weeks post transplantation. Endoscopic improvement was seen in two patients with extensive CD localized in the colon whereas no significant improvement was seen in two patients with ileal CD. Conclusion: Administration of autologous bone marrow derived Mesenchymal Stem Cells seems to be safe and feasible in the treatment of refractory CD, no serious adverse events were detected during harvesting and study follow up. In addition, both clinical and endoscopic efficacy was observed.
Prospective Observation of Quality of Life in Patients with Ulcerative Colitis Undergoing the Ileoanal Pouch Anastomosis Jeanne Tung, William A. Faubion, Edward V. Loftus, Eric Tibesar, John H. Pemberton, Robert R. Cima, David W. Larson, Eric J. Dozois, Bruce G. Wolff, Heidi Nelson, William S. Harmsen, Alan R. Zinsmeister, William J. Sandborn Introduction: Prospective descriptions of quality of life (QOL) in patients (pts) with ulcerative colitis (UC) undergoing the ileal pouch-anal anastomosis (IPAA) are sparse. The aim of this study was to describe the QOL in pts prior to surgery, and 1 year after completion of the IPAA. Method: From January 1-December 31, 2005, adult pts with UC undergoing a colectomy were enrolled (“surgical arm”). Disease activity was assessed with the Ulcerative Colitis Activity Index (UCAI). QOL was assessed with the IBDQ preoperatively, 6 and 12 months after IPAA completion. A functional outcomes questionnaire was administered at 6 and 12 months. UC pts not requiring surgery were also enrolled (“medical arm”) during the study period. These pts filled out the IBDQ at time of entry, and 6 and 12 months later. Results: During the study period, 103 medical pts and 57 surgical pts were enrolled. In the surgical arm, the mean age at study entry was 40.7 yr [SD, 12.2], and 35 were males (61%). Thirteen pts (23%) underwent colectomy for dysplasia. Thirty-five patients completed the 6-month questionnaire, 29 completed the 12-month questionnaire, and 24 completed both. In the medical arm, the mean age was 43.5 yr [SD, 16.7], and 55 were males (53%). Eighty-seven completed the 6 month questionnaire, 79 completed the 12 month questionnaire, and 78 completed both. At baseline, 44 (81%) surgical pts and 39 (38%) medical had active disease. The mean IBDQ score in the surgical arm was 114 (44-216) preoperatively, with a mean increase of 45.7 points at 6 months (p <0.0001), and 53.4 points at 12 months (p <0.0001). Active disease at baseline was associated with higher IBDQ scores at 12 months. At baseline, the mean IBDQ score of pts with dysplasia was 70 points higher than pts without dysplasia (p <0.001). These pts had a nonsignificant trend of lower IBDQ scores at 6 and 12 months. In the surgical pts, >8 stools/day was associated with a lower IBDQ score at both 6 (16/36 pts, 44%) and 12 months (10/29 pts, 35%). Steroid use at baseline in the surgical pts (n=33, 58%) was associated with lower IBDQ scores at baseline, but improved IBDQ scores at 12 months. The mean IBDQ score in the medical arm was 169 (80-224) at study entry, with a mean decrease of 10 points at 6 months (p<0.006), and 9.4 points at 12 months (p <0.01). Conclusions: Pts with UC undergoing IPAA have improved QOL scores by 6 months. Pts requiring steroids preoperatively have improved QOL scores at 12 months. Having >8 stools/day postoperatively is associated with lower QOL scores. Pts undergoing IPAA for colorectal neoplasia have higher IBDQ scores at baseline, but a nonsignificant trend of lower scores at follow-up.
W1089 Safety of Adalimumab in Global Clinical Trials of Patients with Crohn's Disease Jean-Frederic Colombel, Paul Rutgeerts, William J. Sandborn, Paul J. Rutgeerts, Stephen B. Hanauer, Walter Reinisch, Paul F. Pollack, Jeffrey D. Kent, Alexandra T. Cardoso, Winnie Lau Introduction: Adalimumab (ADA), a fully human anti-tumor necrosis factor (anti-TNF) monoclonal antibody, is approved for treating patients (pts) with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy.
A-651
AGA Abstracts
AGA Abstracts
reviewed for patients with IBD treated with mesalamine. Creatinine clearance was calculated by the Modification of Diet in Renal Disease (MDRD) Study Equation and Cockcroft- Gault (CG) Equation at baseline (the first recorded value) and > 1 yr of follow-up. A control group included pts with IBD not treated with mesalamine with > 1 yr follow-up. Results: There were 155 pts with IBD (mean duration: 12.9 yrs, range: 1-45 yrs) who were treated with mesalamine identified (96 with Crohn's disease and 69 with ulcerative colitis). Among them, 75 were female and the mean age was 40.0 yrs (range 18-81 yrs). The mean follow-up in this group was 4.2 yrs (range: 0.6-9.5 yrs). The mean duration of therapy with mesalamine was 10.7 yrs. The control group included 30 pts with IBD (mean duration: 13.9 yrs, range: 2-37 yrs). Among them, 14 were female and mean age was 38.9 yrs (range: 20-66 yrs). The mean follow-up in this cohort was 3.8 yrs (range: 1.0-8.6 yrs). Results are in table 1 (mean values ± SD). There was a statistically significant difference between pts on low and medium dose mesalamine regarding creatinine clearance monitored by CG equation both at baseline and after follow-up (p<0.01). The annual change in serum creatinine (a rather insensitive test) was not statistically altered compared to baseline. Conclusions: The results of our study suggest that long-term use of mesalamine may cause deterioration in renal function. Future prospective studies on large pt cohorts are required to fully validate our findings. Table 1. Creatinine and creatinine clearance at baseline and at follow-up
W1088 Autologous Bone Marrow Derived Mesenchymal Stem Cell Treatment in Patients Refractory Crohn's Disease Patients Marjolijn Duijvestein, Marthe H. Verwey, Herma H. Fidder, Gijs R. van den Brink, Helene Roelofs, Jaap Jan Zwaginga, Willem E. Fibbe, Daniel Hommes
*Including lymphoma and nonmelanoma skin cancer. †Excluding tuberculosis. E=events. W1090
Despite the improvements in Crohn's Disease (CD) management with introduction of antiTNF compounds, a proportion of patients suffer from a poor quality of life due to disease relapse, repeat surgery, extraintestinal manifestations and drug side-effects. Mesenchymal Stem Cells (MSCs) are pluripotent cells that have potent immunosuppressive effects on T and B cells In Vitro and in animal models of chronic inflammation. Promising results have been obtained in patients with steroid resistant, acute and severe graft versus host disease (GvHD), including GvHD of the gut. The objective of this study is to determine the safety and feasibility of autologous bone marrow derived MSC therapy in patients with refractory CD. Methods: 8 adult patients (6 females/2 males, median age 33,5 years) with refractory, moderate to severe CD with a Crohn's Disease Activity Index (CDAI) score of at least 220 underwent bone marrow aspiration (100 ml) under local anesthesia. Mononuclear cells were isolated by density gradient centrifugation and plated in culture medium containing 10% Fetal Calf Serum. MSCs were expanded in culture until passage 1-3. To date, five patients received 2 doses of 1-2 million cells/kg bodyweight, intravenously, 7 days apart. Primary outcomes were feasibility and safety of autologous MSC expansion and infusion. Secondary outcomes were changes in the CDAI score and Crohn's Disease Endoscopic Index of Severity Score (CDEIS). Results: MSC from CD patients showed the typical spindle-shaped morphology and similar growth potential and yield comparable to MSCs from healthy donors (n= 8). The initial median CDAI score in the first five patients treated was 334 (range 254-350). MSC infusion was successful and without side effects, with exception of a mild allergic reaction to the cryopreservant dimethyl sulfoxide (DMSO) in one patient. The first patient was a chronic severe steroid refractory patient on the waiting list for surgery. Although an initial drop of CDAI was seen, she was operated upon due to poor general condition and persistent rectal blood loss. The other four treated patients showed an average decrease in median CDAI score of 107 points 6 weeks post transplantation. Endoscopic improvement was seen in two patients with extensive CD localized in the colon whereas no significant improvement was seen in two patients with ileal CD. Conclusion: Administration of autologous bone marrow derived Mesenchymal Stem Cells seems to be safe and feasible in the treatment of refractory CD, no serious adverse events were detected during harvesting and study follow up. In addition, both clinical and endoscopic efficacy was observed.
Prospective Observation of Quality of Life in Patients with Ulcerative Colitis Undergoing the Ileoanal Pouch Anastomosis Jeanne Tung, William A. Faubion, Edward V. Loftus, Eric Tibesar, John H. Pemberton, Robert R. Cima, David W. Larson, Eric J. Dozois, Bruce G. Wolff, Heidi Nelson, William S. Harmsen, Alan R. Zinsmeister, William J. Sandborn Introduction: Prospective descriptions of quality of life (QOL) in patients (pts) with ulcerative colitis (UC) undergoing the ileal pouch-anal anastomosis (IPAA) are sparse. The aim of this study was to describe the QOL in pts prior to surgery, and 1 year after completion of the IPAA. Method: From January 1-December 31, 2005, adult pts with UC undergoing a colectomy were enrolled (“surgical arm”). Disease activity was assessed with the Ulcerative Colitis Activity Index (UCAI). QOL was assessed with the IBDQ preoperatively, 6 and 12 months after IPAA completion. A functional outcomes questionnaire was administered at 6 and 12 months. UC pts not requiring surgery were also enrolled (“medical arm”) during the study period. These pts filled out the IBDQ at time of entry, and 6 and 12 months later. Results: During the study period, 103 medical pts and 57 surgical pts were enrolled. In the surgical arm, the mean age at study entry was 40.7 yr [SD, 12.2], and 35 were males (61%). Thirteen pts (23%) underwent colectomy for dysplasia. Thirty-five patients completed the 6-month questionnaire, 29 completed the 12-month questionnaire, and 24 completed both. In the medical arm, the mean age was 43.5 yr [SD, 16.7], and 55 were males (53%). Eighty-seven completed the 6 month questionnaire, 79 completed the 12 month questionnaire, and 78 completed both. At baseline, 44 (81%) surgical pts and 39 (38%) medical had active disease. The mean IBDQ score in the surgical arm was 114 (44-216) preoperatively, with a mean increase of 45.7 points at 6 months (p <0.0001), and 53.4 points at 12 months (p <0.0001). Active disease at baseline was associated with higher IBDQ scores at 12 months. At baseline, the mean IBDQ score of pts with dysplasia was 70 points higher than pts without dysplasia (p <0.001). These pts had a nonsignificant trend of lower IBDQ scores at 6 and 12 months. In the surgical pts, >8 stools/day was associated with a lower IBDQ score at both 6 (16/36 pts, 44%) and 12 months (10/29 pts, 35%). Steroid use at baseline in the surgical pts (n=33, 58%) was associated with lower IBDQ scores at baseline, but improved IBDQ scores at 12 months. The mean IBDQ score in the medical arm was 169 (80-224) at study entry, with a mean decrease of 10 points at 6 months (p<0.006), and 9.4 points at 12 months (p <0.01). Conclusions: Pts with UC undergoing IPAA have improved QOL scores by 6 months. Pts requiring steroids preoperatively have improved QOL scores at 12 months. Having >8 stools/day postoperatively is associated with lower QOL scores. Pts undergoing IPAA for colorectal neoplasia have higher IBDQ scores at baseline, but a nonsignificant trend of lower scores at follow-up.
W1089 Safety of Adalimumab in Global Clinical Trials of Patients with Crohn's Disease Jean-Frederic Colombel, Paul Rutgeerts, William J. Sandborn, Paul J. Rutgeerts, Stephen B. Hanauer, Walter Reinisch, Paul F. Pollack, Jeffrey D. Kent, Alexandra T. Cardoso, Winnie Lau Introduction: Adalimumab (ADA), a fully human anti-tumor necrosis factor (anti-TNF) monoclonal antibody, is approved for treating patients (pts) with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy.
A-651
AGA Abstracts
AGA Abstracts
reviewed for patients with IBD treated with mesalamine. Creatinine clearance was calculated by the Modification of Diet in Renal Disease (MDRD) Study Equation and Cockcroft- Gault (CG) Equation at baseline (the first recorded value) and > 1 yr of follow-up. A control group included pts with IBD not treated with mesalamine with > 1 yr follow-up. Results: There were 155 pts with IBD (mean duration: 12.9 yrs, range: 1-45 yrs) who were treated with mesalamine identified (96 with Crohn's disease and 69 with ulcerative colitis). Among them, 75 were female and the mean age was 40.0 yrs (range 18-81 yrs). The mean follow-up in this group was 4.2 yrs (range: 0.6-9.5 yrs). The mean duration of therapy with mesalamine was 10.7 yrs. The control group included 30 pts with IBD (mean duration: 13.9 yrs, range: 2-37 yrs). Among them, 14 were female and mean age was 38.9 yrs (range: 20-66 yrs). The mean follow-up in this cohort was 3.8 yrs (range: 1.0-8.6 yrs). Results are in table 1 (mean values ± SD). There was a statistically significant difference between pts on low and medium dose mesalamine regarding creatinine clearance monitored by CG equation both at baseline and after follow-up (p<0.01). The annual change in serum creatinine (a rather insensitive test) was not statistically altered compared to baseline. Conclusions: The results of our study suggest that long-term use of mesalamine may cause deterioration in renal function. Future prospective studies on large pt cohorts are required to fully validate our findings. Table 1. Creatinine and creatinine clearance at baseline and at follow-up