- Email: [email protected]
943b Induction Therapy for Ulcerative Colitis: Results of GEMINI I, a Randomized, Placebo-Controlled, Double-Blind, Multicenter Phase 3 Trial
AGA Abstracts
cultured crypts/organoids. The COX-2 inhibitor NS-398 (10 uM) caused a significant decrease in the budding and survival of mouse colonic organoids (n=4, p<0.05) and also caused a reduction in proliferation of human colonic crypts. Furthermore, PGE2 (1 uM) caused a 1.5 fold increase in proliferation at the base of human colonic crypts, and also rescued Cox2 suppression of crypt cell proliferation (n>5, p<0.05). PGE2 increased the number of LGR5/ OLFM4+ cells along the human crypt axis and inhibition of COX-2 by NS-398 reduced the number of LGR5/OLFM4+ cells along the crypt axis, which was rescued by PGE2 (n>5, p<0.05). Use of EP1-4 receptor antagonists showed differential effects on mouse organoid formation and survival. Inhibition of EP2 and 4 had no effect (n=2), however inhibition of EP1 and EP3 showed a significant reduction in organoid survival and budding (n=3, P<0.05). Of note, tissue obtained from IBD sufferers was characterised by internalisation of EP1-4 receptors and an increased number of OLFM4+ stem/progenitor cells. CONCLUSIONS: PGE2 supports the proliferation, growth and survival of cultured human and mouse crypt/ organoids and maintains intestinal stem/progenitor cells. This effect is mediated in part by activation of EP1 and EP3 receptor subtypes. Ongoing work is investigating the effects of EP receptor inhibition on crypt cell dynamics in IBD.
1. H2B-GFP-retaining cells, majority with characteristics of slow cycling stem cells, were consistently seen above the Paneth cell zone of the small intestine. 2. Whilst a proportion were sensitive to low dose radiation-induced cell death, the majority were resistant to low and high dose radiation. Subpopulations of surviving H2B-GFP-retaining cells proliferated during subsequent small intestinal mucosal regeneration. Thus, our studies suggest that H2B-GFP-retention identifies slow cycling stem cells that re-establish normal small intestinal epithelial function after injury. 3. H2B-GFP-retaining epithelial cells with the above characteristics were not seen in the colon, implying important differences in stem cell function between these two regions of the gastrointestinal tract, which may have implications for region-specific susceptibility to diseases in which epithelial stem cells and their progeny are involved. Percentage of cell position (cp) 4 cells retaining H2B-GFP
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Malignantly Transformed Bone Marrow-Derived Mesenchymal Stem Cells Promote CD44 Positive Epithelial Cell Proliferation and the Development of Gastrointestinal Stromal-Type Tumors Jessica M. Donnelly, Gregory P. Boivin, Jean Marie Houghton, Yana Zavros
Oral Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Noncancer Pain R.L. Rauck, J.F. Peppin, R.J. Israel, J. Carpenito, J. Cohn, S. Huang, E. Bortey, C. Paterson, W.P. Forbes
BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are known to sustain cancer cells by creating a microenvironment favorable for tumor growth and immunosuppression of the host immune response. Gastric cancer is associated with the recruitment of bone marrow-derived cells, and although it isn't clear which cell type within the bone marrow is contributing, it appears to be a mesenchymal stem cell that has undergone mutation and malignant transformation. The current study uses transplantation of an In Vitro malignantly transformed mesenchymal stem cell line (stMSC) to accelerate cancer progression that In Vivo would normally occur over several years with chronic inflammation. Within the tumor microenvironment, Sonic Hedgehog (Shh) is elevated and may originate from recruited stMSCs. CD44 positive cells are induced to proliferate, and nuclear CD44/ acetylated-STAT3 generates cells with properties of cancer stem cells that drive tumor development. The mechanism regulating CD44 positive cells in the progression of gastric cancer is unclear. HYPOTHESIS: Shh secreted by recruited bone marrow-derived stMSCs stimulates the aberrant proliferation of CD44 positive cancer stem-like cells. METHODS: RFP-expressing stMSCs were transduced with lentiviral constructs containing a vector control (stMSCVect) or shRNA targeting the Shh gene (stMSCShhKO). The role of stMSCs in promoting cancer progression was identified using gastric submucosal transplantation of C57BL/6 control or gastrin-deficient (GKO) mice with stMSCVect or stMSCShhKO cells and analysis 60 days post-transplantation. Cytokine and chemokine profiles of BM-MSCs versus stMSCs and gastric biopsies from transplanted mice were analyzed by qRT-PCR. RESULTS: Compared to stMSCsShhKO transplanted mice, within the inflamed GKO mouse stomach Shh-expressing stMSCsVect induced proliferation of CD44-positive cells and tumor development. Neoplasms in this experimental group were characterized by pleomorphic spindle-shaped cells with high mitotic activity. CD44 positive cells in the gastric mucosa expressed Shh receptor Patched and the CD44 isoform, CD44v6, was uniquely associated with tumor stroma. Elevated Shh within the gastric epithelium of stMSCsVect transplanted GKO mice coincided with increased IFNγ responsive Signal Transducer and Activator of Transcription (STAT) protein, reflected by increased phosphorylated STAT1 and STAT3 expression. Shh expression from stMSCs was also required for the upregulation of pro-inflammatory cytokines, such as TGFβ and IL-6, within the mucosa suggesting a Shh-mediated autocrine mechanism regulating the immune profile of these cell lines. CONCLUSION: Shh secreted from stMSCs mediates the immunomodulatory phenotype of stMSCs and provides a proliferative stimulus for Hedgehog-responsive CD44-positive gastric epithelial cells that contribute to tumor growth.
Background: Opioid use for chronic, noncancer pain may be complicated by dose-limiting opioid-induced constipation (OIC), impacting quality of life and pain control. Methylnaltrexone (MNTX) is a peripherally acting, selective -opioid receptor antagonist approved in > 50 countries worldwide as a subcutaneous (SC) injection for the treatment of OIC in patients with advanced illness (RELISTOR®). Oral MNTX represents a 1st in class and potential new oral therapy for the treatment of OIC in subjects with chronic, noncancer pain. Purpose: Evaluate the safety and efficacy of MNTX administered in an oral formulation in a phase 3, double-blind, placebo (PBO)-controlled, parallel-group, dose ranging, multicenter study. Methods: 804 subjects were randomized to receive PBO or oral MNTX tablets 150, 300, or 450mg for 12 weeks (4 weeks QD followed by 8 weeks PRN dosing). Subjects were taking ≥ 50mg oral morphine equivalents/day for ≥ 1 month for chronic, noncancer pain and had a history of OIC. Primary endpoint was the percentage of doses resulting in rescuefree bowel movement (RFBM) within 4 hours (h) of dosing during the 4-week QD dosing period. Rescue-free was defined as no laxative use within 24h prior to bowel movement. Key secondary endpoints were 1) proportion of subjects with ≥ 3 RFBMs/week and ≥ 1 RFBM/week increase from baseline for ≥ 3 of 4 weeks and 2) change in weekly RFBMs from baseline during QD dosing. Results: Demographic and baseline characteristics were similar among groups. For the primary endpoint, a significantly greater proportion of subjects in the 300 and 450mg dose groups experienced RFBMs within 4h of dosing compared with PBO over the 28 days of QD dosing. These findings were maintained throughout the entire 12 weeks including QD and PRN phases. Significant differences were also seen for ≥ 3 RFBMs/week with an increase of ≥ 1/week over baseline at the 300 and 450mg doses during the 28 day QD dosing (Table 1). Analyses based on the primary endpoint demonstrated a linear dose response for the 3 active doses (p<.0001) over 28 days of QD dosing. For the first dose (Figure 1), significant differences were seen in the 150 (34%), 300 (41%) and 450mg (42%) treatment groups for RFBM by 24h post first dose compared with subjects receiving PBO (23%) (p=0.0200, p=0.0002, p<.0001, respectively). The incidence of adverse events (AE) was similar among treatment groups and PBO: most common AEs (≥ 3%) were abdominal pain (6.0% PBO, 6.8% all MNTX), nausea (5.5%, 4.7%), flatulence (4.5%, 4.0%) and diarrhea (2.0%, 3.3%). Conclusions: Oral MNTX 150, 300 and 450mg QD significantly increased the proportion of RFBMs and decreased time to first RFBM in a dose-dependent manner in patients with OIC. Efficacy of oral MNTX in this study was comparable to that reported in clinical studies of SC MNTX in subjects with chronic, noncancer pain.
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Doxycycline-Induced Histone 2B (H2B)-Green Fluorescent Protein (GFP)Retaining Putative Stem Cells Participate in Small Intestinal Regeneration, but are Absent in the Colon Kevin R. Hughes, Ricardo Gândara, Tanvi Javkar, Fred Sablitzky, Hanno Hock, Christopher Potten, Yashwant R. Mahida
Induction Therapy for Ulcerative Colitis: Results of GEMINI I, a Randomized, Placebo-Controlled, Double-Blind, Multicenter Phase 3 Trial B.G. Feagan, P.J. Rutgeerts, B.E. Sands, J. Colombel, W.J. Sandborn, J. Colombel, S.B. Hanauer, G.A. Van Assche, J. Axler, H. Kim, S. Danese, I. Fox, C. Milch, S. Sankoh, T. Wyant, J. Xu, A. Parikh
Stem cells have been identified in two locations in small intestinal crypts, those intercalated between Paneth cells and another population (which retains DNA label) is located above the Paneth cell zone, at cell position (cp) 4. Because of disadvantages associated with the use of DNA label, we investigated the utility of doxycycline-induced transient transgenic expression of histone 2B (H2B)-green fluorescent protein (GFP) in TetOP-H2B-GFP mice (Nat Biotechnol. 2009;27:84-90). Methods. Following doxycycline-induced expression of H2B-GFP in all intestinal epithelial cells, retention of label was studied at varying time periods of chase, including post-irradiation. To study DNA-label retaining cells (LRCs) bromodeoxyuridine (BrdU) was administered for 7 days. Expression of GFP, BrdU, lysozyme, caspase 3 (identifies apoptotic cells) and phospho-histone H3 (phH3; expressed in mitosis) was studied by immunohistochemistry, double immunofluorescence and flow cytometry. Data are presented as mean(±SEM). Results. Over chase periods of up to 112 days, H2BGFP-retaining cells (with peak at cp4) were consistently seen above the Paneth cell zone in the small intestine (Table). After 14 and 28 day chase, there were significantly greater proportions of H2B-GFP-retaining cp4 cells than BrdU (DNA)-LRCs (BrdU: 6.4(±0.5)% & 3.8(±0.6)% vs data in Table; p<0.05). Majority of the BrdU-retaining non-Paneth cells also retained H2B-GFP after 14 day [86.7(±6.7)%] and 28 day [66.7(±16.7)%] chase. Post(4.5 h)-irradiation, 26.1(±11.5)% (1 Gy) and 34.6(±8.2)% (8 Gy) of H2B-GFP-retaining nonPaneth cells were apoptotic. Percentage of non-Paneth H2B-GFP-retaining cells expressing phH3 after 28 day chase: non-irradiated - 7.8(±1.4)%; after 12 Gy irradiation - 39.5(±6.2)% (24 h), 31.0(±7.6)% (48 h), 31.1(±5.9)% (72 h). In contrast to small intestine, no H2B-GFPretaining epithelial cells were seen in the colon from 28 day chase onwards. Conclusions.
AGA Abstracts
Aim: To assess the efficacy and safety of vedolizumab (VDZ), a gut-selective monoclonal antibody targeting the α4β7 integrin, as induction therapy in patients with moderate to severely active ulcerative colitis (UC) in whom at least one prior therapy had failed. Methods: The trial had both an induction and a maintenance phase; each phase was treated as an independent study for statistical analyses. The primary outcome of the induction phase was to determine the effect of VDZ treatment on clinical response (defined as a reduction in complete Mayo score of ≥3 points and ≥30% from baseline, along with a decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of ≤1 point) at 6 weeks. Secondary outcomes were to determine the effect of VDZ induction treatment on clinical remission (complete Mayo score of ≤2 points and no individual subscore >1 point) and mucosal healing (Mayo endoscopic subscore of ≤1 point) at 6 weeks. Patients with a Mayo score of ≥6 and an endoscopic subscore of ≥2 despite treatment with corticosteroids, purine antimetabolites, and/or TNFα antagonists were randomized 3:2 to receive either vedolizumab 300 mg IV or placebo on days 1 and 15. Results: The induction phase intent-to-treat (ITT) population comprised 374 patients (mean age 40.5 yrs; mean disease duration 6.5 yrs; mean baseline Mayo score 8.6). Of these, 225 received VDZ and 149 received placebo. A significantly greater proportion of VDZ-treated patients achieved clinical response, remission, and mucosal healing at 6 weeks, compared with placebo (Table 1). 39% of the ITT population had prior anti-TNFα failure. Clinical response and remission rates were higher in VDZ than placebo patients among both those
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943e MuDelta Treatment Improves Bowel Movement Frequency and Urgency Episodes in Patients with Diarrhea-Predominant Irritable Bowel Syndrome: Results of a Phase 2 Clinical Trial P.S. Covington, D. Andrae, S. Dove, C.W. Randall, C.W. Randall, J. Davenport, G. McIntyre, J. Almenoff Introduction: Simultaneously targeting mu and delta opioid receptors in the gastrointestinal tract may provide symptom relief for sufferers of diarrhea-predominant irritable bowel syndrome (IBS-d) without the constipating effects of a pure mu opioid agonist. We completed a double-blind, placebo-controlled, Phase 2 study of a minimally-absorbed, mu opioid agonist/delta opioid antagonist (MuDelta) within which we recruited patients meeting the Rome III criteria for IBS-d. Efficacy from this trial as measured by a composite outcome of stool consistency and pain measures have been previously reported and here outcomes related to patient-reported daily number of bowel movements (BMs) and urgency episodes (UEs) are presented. Methods: A total of 807 patients with IBS-d were enrolled and randomized to twice daily treatment with placebo or MuDelta doses of 5, 25, 100, or 200 mg for 12 weeks (approximately 84 days). Patients rated their BMs, UEs and other symptoms via daily diary calls to an interactive voice response system. Analyses of patients’ BM and UE frequencies were conducted via fitting longitudinal generalized linear mixed effects models to account for repeated reports by each patient. Fixed effects fit included treatment, study day, baseline average daily BM/UE values, the treatment by study day interaction, quadratic and cubic effects for study day, and the treatment by quadratic interaction for study day. A random effect was also fit to account for the repeated measurements of individuals. Higher-order time effects were fit to account for nonlinearity observed in the data over time. Estimates of BM and UE frequency as well as relative risk (RR) were computed at 28, 56, and 84 days post-baseline. Results: Summary results of the analyses are presented in Table 1. Of the total enrolled, 754 patients met the predefined intention-to-treat definition and their data were fit with the statistical models. Comparing 100 mg of MuDelta to placebo, mean BM frequency was shown to be consistently less for the 100 mg group over the course of 28 days (RR=0.90, p=.032), and significantly less over 56 days (RR=0.91, p=.042), and 84 days (RR=0.85, p= .002) of treatment. Mean UE frequency results decreased significantly for the 100 mg group over placebo at 28 days (RR=0.77, p=.021), 56 days (RR=0.79, p=.032), and 84 days (RR= 0.75, p=.012). Further, 200 mg also showed significant results for BM & EU frequency at 28 days (RR=0.81, p<.001 & RR=0.69, p<.001), 56 days (RR=0.84, p<.001& RR=0.73, p= .005), and 84 days (RR=0.87, p<.001 & RR=0.79, p=.050) as compared to placebo, respectively. Conclusion: These results indicate that MuDelta provides statistically significant and clinically meaningful efficacy in improving bowel frequency and urgency in patients with IBS-d. Research funding was provided by Furiex Pharmaceuticals.
943c ACCELERATED STEP-CARE THERAPY WITH EARLY AZATHIOPRINE (AZA) VS. CONVENTIONAL STEP-CARE THERAPY IN CROHN’S DISEASE. A RANDOMIZED STUDY. J. Cosnes, A. Bourrier, Y. Bouhnik, D. Laharie, S. Nahon, J. Bonnet, G. Getaid, F. Carbonnel, J. Dupas, R. Jean Marie, P. Jouet, G. Savoye, J. Mary, J. Colombel In early Crohn’s disease (CD) patients at risk for disabling disease, two possible treatment strategies are considered as potentially highly effective : accelerated step-care (steroids + AZA) or early combined immunosuppression (anti-TNF + AZA). However the accelerated step-care strategy (early AZA) has been poorly explored. The aim of this randomized, openlabel, controlled trial was to compare an early AZA approach with conventional step-care therapy in early CD. Methods: patients with a diagnosis of CD of less than 6mos, naive to immunosuppressors and biologics, with no previous history of surgery and having at least two predictors of disabling disease were randomized to receive AZA 2.5mg/kg at inclusion (e-AZA) or on demand according to guidelines (Controls). Predictors of disabling CD included an age<40 years, active perianal disease within the first 6 mos and need for oral steroids within the first 3 mos1. Patients were included in 24 GETAID centres between 2005, July, and 2010, December. The primary endpoint was the proportion of trimesters spent in steroid-free and anti-TNF-free remission during the first 3 years after inclusion. Data were compared between e-AZA and Control groups using non-parametric tests. Results: 147 patients were randomized to e-AZA or to Controls. Five patients were excluded just after inclusion, leaving 142 patients (71 e-AZA, 71 Controls) with a median (IQR) follow-up of 35 mos (15-36) at the reference date of on-going follow-up (2011, October 1). They were 71 M and 71 F with median age (IQR) of 27 yrs (22-29) and a median disease duration of 2.5 months (1-3.7). 42 Controls (62%) required immunosuppressors during follow-up after a median time of 5.6 months (3.2-9.6). The proportion of trimesters in remission (median, IQR) was 61% (12-83) in e-AZA patients, vs. 50% (30-72) in Controls (NS). Additionally, 19 e-AZA patients (29%) required anti-TNF vs.18 Controls (26%, NS), 2 (3%) had unplanned surgical perianal procedures vs. 9 Controls (13%, p 0.055), and 7 (11%) had intestinal surgery vs. 14 Controls (21%, p 0.11). Median values of mean CDAI and C-reactive protein did not differ between the 2 groups. Conclusion: in patients at risk for disabling CD, early AZA was not associated with a significantly increased clinical remission rate during the first years of CD. More than one third of control patients had a mild-to-moderate course not requiring immunosuppressors at a 3 year follow-up. These data do not support the widespread use of an accelerated stepcare strategy compared to conventional step-care. 1 Beaugerie et al. Gastroenterology 2006; 130: 650-6
943f TMC435 in HCV Genotype 1 Patients Who Have Failed Previous Pegylated Interferon/Ribavirin Treatment: Final SVR24 Results of The ASPIRE Trial F. Poordad, S. Zeuzem, T. Berg, E. Gane, P. Ferenci, G. Foster, M.W. Fried, C. Hezode, G. Hirschfield, I.M. Jacobson, I. Nikitin, P.J. Pockros, O. Lenz, M. Peeters, V. Sekar, G. De Smedt, M. Beumont-Mauviel
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Purpose: ASPIRE (TMC435-C206; NCT00980330) was an international, Phase IIb, randomized, double-blind, placebo-controlled trial investigating the efficacy, tolerability, safety and pharmacokinetics of TMC435 (an oral, once-daily, investigational HCV NS3/4A protease inhibitor) administered with peginterferon/ribavirin (P/R). Here we report the final SVR24 results of the ASPIRE trial. Methods: Patients were chronically-infected with HCV genotype 1, with documented evidence of null-response (<2 log10 reduction Week 12), partial response (≥2 log10 reduction Week 12; detectable end-of-treatment) or relapse (undetectable end of treatment; detectable within 24 weeks post-treatment) following ≥1 course of P/R therapy. Patients were randomized to one of seven treatment arms: TMC435 (100 or 150mg once-daily) for 12, 24 or 48 weeks in combination with 48 weeks of P/R, or placebo with P/R for 48 weeks. Results: Of 462 patients enrolled, 19% had metavir score F3 and 18% F4, 41% were infected with genotype 1a and 58% 1b. Overall, in TMC435-treated patients SVR24 rates were higher (61-80%; Table) compared with control (23%), and in F4 prior null-responders were 3146% (control 0%). In TMC435 groups, discontinuation due to viral breakthrough or lack of on-treatment response was 9-17% (control 53%), and viral relapse occurred in 6-18% (control 44%). Incidence of adverse events leading to treatment discontinuation and serious adverse events was similar across all groups. Mild, transient, asymptomatic bilirubin increases were observed with TMC435, with no significant differences between 100mg and 150mg doses. Conclusions: Following treatment with TMC435 plus P/R, patients who failed previous P/ R treatment exhibited significantly higher SVR24 rates compared with placebo, including difficult-to-treat prior null-responders with cirrhosis. TMC435 was well tolerated in this population.
A Phase 2/3 Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Subcutaneous Golimumab Induction Therapy in Patients with Moderately to Severely Active Ulcerative Colitis: PURSUIT SC W.J. Sandborn, B.G. Feagan, C.W. Marano, R. Strauss, J. Johanns, H. Zhang, J. Colombel, W. Reinisch, P. Gibson, J. Collins, G.A. Jarnerot, P.J. Rutgeerts Objective: To evaluate the safety and efficacy of subcutaneous (SC) golimumab (GLM) induction therapy in patients with moderately to severely active ulcerative colitis (UC) despite current adequate treatment or who had previously failed to respond to or tolerate treatment with 6-MP, AZA, corticosteroids and/or 5-ASAs or were corticosteroid dependent and were naïve to anti-TNF therapy. Methods: PURSUIT SC had an adaptive design with Phase 2 dose ranging followed by a confirmatory Phase 3 component. Patients with Mayo scores of 6-12 inclusive, including endoscopic subscore ≥2 were randomized to receive placebo(PBO)/PBO; GLM 100mg/50mg (before dose selection only); GLM 200mg/100mg; GLM 400mg/ 200mg at wks 0 and 2. The primary endpoint was clinical response at wk6 in patients enrolled after dose selection. Secondary endpoints at wk6 were clinical remission, mucosal healing, and change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ). The primary analysis population for efficacy consisted of patients randomized after dose selection (n=774); for safety, all treated patients in Phase 2 and Phase 3 were combined (n=1065). Results: 774 patients were randomized to treatment in the primary analysis population; 759 patients (98%) completed through wk6. Baseline demographics, UC disease characteristics and concomitant UC medications were similar among treatment groups. Significantly higher proportions of patients who received GLM were in clinical response, clinical remission, mucosal healing and showed improvement in the IBDQ at wk6 compared to PBO-treated patients (Table). Through wk6, the proportions of patients with AEs were similar for the combined GLM and placebo groups (39.1% and 38.2%, respectively); 3.0% and 6.1% of patients, respectively, had a serious AE. Similar rates were observed in the GLM200/100mg and GLM400/200mg groups. A death occurred in a patient in the GLM400mg/200 mg group; a single case of demyelination was reported for a patient in this group. Injection site reactions were uncommon and comparable across GLM groups. Malignancy rates were 0.3%. 0.0%, and 0.3% in the PBO, GLM200mg/100mg, and GLM400/200mg groups, respectively. Conclusion Induction regimens of SC GLM induced clinical response, clinical remission, mucosal healing and improved quality of life in anti-TNF naïve patients with moderately to severely active UC, who have had an inadequate response to conventional UC medication. The safety of GLM induction in UC was consistent with the safety profile of GLM in labeled rheumatologic indications and other anti-TNFs.
944 Transient Elastography as a Tool to Look for Total Parenteral NutritionInduced Liver Complications Myriam Dumas-Campagna, Louise D'Aoust, Michel Lemoyne, Catherine Vincent Introduction: Intrahepatic cholestasis is a potential complication of long-term total parenteral nutrition (TPN), which can progress to fibrosis. Transient elastography is a non-invasive procedure that evaluates liver fibrosis through measurement of liver stiffness. Our aim was to evaluate the feasibility and the biochemical correlations of transient elastography in a population of patients on chronic TPN. Methods: Transient elastography was performed in long-term TPN patients during their follow-up at Hôpital Saint-Luc du CHUM (Centre
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AGA Abstracts
AGA Abstracts
with prior anti-TNF failure and those with no prior anti-TNF exposure (Table 2). In preliminary analyses through week 6, rates of adverse events (AEs), serious AEs, and serious infectious AEs were similar between VDZ and placebo groups. Conclusions: Induction therapy with VDZ was significantly more effective than placebo in achieving clinical response, clinical remission, and mucosal healing in a population of UC patients with a high rate of prior anti-TNF failure. Similar rates of AEs were observed in the VDZ and placebo groups.
cultured crypts/organoids. The COX-2 inhibitor NS-398 (10 uM) caused a significant decrease in the budding and survival of mouse colonic organoids (n=4, p<0.05) and also caused a reduction in proliferation of human colonic crypts. Furthermore, PGE2 (1 uM) caused a 1.5 fold increase in proliferation at the base of human colonic crypts, and also rescued Cox2 suppression of crypt cell proliferation (n>5, p<0.05). PGE2 increased the number of LGR5/ OLFM4+ cells along the human crypt axis and inhibition of COX-2 by NS-398 reduced the number of LGR5/OLFM4+ cells along the crypt axis, which was rescued by PGE2 (n>5, p<0.05). Use of EP1-4 receptor antagonists showed differential effects on mouse organoid formation and survival. Inhibition of EP2 and 4 had no effect (n=2), however inhibition of EP1 and EP3 showed a significant reduction in organoid survival and budding (n=3, P<0.05). Of note, tissue obtained from IBD sufferers was characterised by internalisation of EP1-4 receptors and an increased number of OLFM4+ stem/progenitor cells. CONCLUSIONS: PGE2 supports the proliferation, growth and survival of cultured human and mouse crypt/ organoids and maintains intestinal stem/progenitor cells. This effect is mediated in part by activation of EP1 and EP3 receptor subtypes. Ongoing work is investigating the effects of EP receptor inhibition on crypt cell dynamics in IBD.
1. H2B-GFP-retaining cells, majority with characteristics of slow cycling stem cells, were consistently seen above the Paneth cell zone of the small intestine. 2. Whilst a proportion were sensitive to low dose radiation-induced cell death, the majority were resistant to low and high dose radiation. Subpopulations of surviving H2B-GFP-retaining cells proliferated during subsequent small intestinal mucosal regeneration. Thus, our studies suggest that H2B-GFP-retention identifies slow cycling stem cells that re-establish normal small intestinal epithelial function after injury. 3. H2B-GFP-retaining epithelial cells with the above characteristics were not seen in the colon, implying important differences in stem cell function between these two regions of the gastrointestinal tract, which may have implications for region-specific susceptibility to diseases in which epithelial stem cells and their progeny are involved. Percentage of cell position (cp) 4 cells retaining H2B-GFP
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Malignantly Transformed Bone Marrow-Derived Mesenchymal Stem Cells Promote CD44 Positive Epithelial Cell Proliferation and the Development of Gastrointestinal Stromal-Type Tumors Jessica M. Donnelly, Gregory P. Boivin, Jean Marie Houghton, Yana Zavros
Oral Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Noncancer Pain R.L. Rauck, J.F. Peppin, R.J. Israel, J. Carpenito, J. Cohn, S. Huang, E. Bortey, C. Paterson, W.P. Forbes
BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are known to sustain cancer cells by creating a microenvironment favorable for tumor growth and immunosuppression of the host immune response. Gastric cancer is associated with the recruitment of bone marrow-derived cells, and although it isn't clear which cell type within the bone marrow is contributing, it appears to be a mesenchymal stem cell that has undergone mutation and malignant transformation. The current study uses transplantation of an In Vitro malignantly transformed mesenchymal stem cell line (stMSC) to accelerate cancer progression that In Vivo would normally occur over several years with chronic inflammation. Within the tumor microenvironment, Sonic Hedgehog (Shh) is elevated and may originate from recruited stMSCs. CD44 positive cells are induced to proliferate, and nuclear CD44/ acetylated-STAT3 generates cells with properties of cancer stem cells that drive tumor development. The mechanism regulating CD44 positive cells in the progression of gastric cancer is unclear. HYPOTHESIS: Shh secreted by recruited bone marrow-derived stMSCs stimulates the aberrant proliferation of CD44 positive cancer stem-like cells. METHODS: RFP-expressing stMSCs were transduced with lentiviral constructs containing a vector control (stMSCVect) or shRNA targeting the Shh gene (stMSCShhKO). The role of stMSCs in promoting cancer progression was identified using gastric submucosal transplantation of C57BL/6 control or gastrin-deficient (GKO) mice with stMSCVect or stMSCShhKO cells and analysis 60 days post-transplantation. Cytokine and chemokine profiles of BM-MSCs versus stMSCs and gastric biopsies from transplanted mice were analyzed by qRT-PCR. RESULTS: Compared to stMSCsShhKO transplanted mice, within the inflamed GKO mouse stomach Shh-expressing stMSCsVect induced proliferation of CD44-positive cells and tumor development. Neoplasms in this experimental group were characterized by pleomorphic spindle-shaped cells with high mitotic activity. CD44 positive cells in the gastric mucosa expressed Shh receptor Patched and the CD44 isoform, CD44v6, was uniquely associated with tumor stroma. Elevated Shh within the gastric epithelium of stMSCsVect transplanted GKO mice coincided with increased IFNγ responsive Signal Transducer and Activator of Transcription (STAT) protein, reflected by increased phosphorylated STAT1 and STAT3 expression. Shh expression from stMSCs was also required for the upregulation of pro-inflammatory cytokines, such as TGFβ and IL-6, within the mucosa suggesting a Shh-mediated autocrine mechanism regulating the immune profile of these cell lines. CONCLUSION: Shh secreted from stMSCs mediates the immunomodulatory phenotype of stMSCs and provides a proliferative stimulus for Hedgehog-responsive CD44-positive gastric epithelial cells that contribute to tumor growth.
Background: Opioid use for chronic, noncancer pain may be complicated by dose-limiting opioid-induced constipation (OIC), impacting quality of life and pain control. Methylnaltrexone (MNTX) is a peripherally acting, selective -opioid receptor antagonist approved in > 50 countries worldwide as a subcutaneous (SC) injection for the treatment of OIC in patients with advanced illness (RELISTOR®). Oral MNTX represents a 1st in class and potential new oral therapy for the treatment of OIC in subjects with chronic, noncancer pain. Purpose: Evaluate the safety and efficacy of MNTX administered in an oral formulation in a phase 3, double-blind, placebo (PBO)-controlled, parallel-group, dose ranging, multicenter study. Methods: 804 subjects were randomized to receive PBO or oral MNTX tablets 150, 300, or 450mg for 12 weeks (4 weeks QD followed by 8 weeks PRN dosing). Subjects were taking ≥ 50mg oral morphine equivalents/day for ≥ 1 month for chronic, noncancer pain and had a history of OIC. Primary endpoint was the percentage of doses resulting in rescuefree bowel movement (RFBM) within 4 hours (h) of dosing during the 4-week QD dosing period. Rescue-free was defined as no laxative use within 24h prior to bowel movement. Key secondary endpoints were 1) proportion of subjects with ≥ 3 RFBMs/week and ≥ 1 RFBM/week increase from baseline for ≥ 3 of 4 weeks and 2) change in weekly RFBMs from baseline during QD dosing. Results: Demographic and baseline characteristics were similar among groups. For the primary endpoint, a significantly greater proportion of subjects in the 300 and 450mg dose groups experienced RFBMs within 4h of dosing compared with PBO over the 28 days of QD dosing. These findings were maintained throughout the entire 12 weeks including QD and PRN phases. Significant differences were also seen for ≥ 3 RFBMs/week with an increase of ≥ 1/week over baseline at the 300 and 450mg doses during the 28 day QD dosing (Table 1). Analyses based on the primary endpoint demonstrated a linear dose response for the 3 active doses (p<.0001) over 28 days of QD dosing. For the first dose (Figure 1), significant differences were seen in the 150 (34%), 300 (41%) and 450mg (42%) treatment groups for RFBM by 24h post first dose compared with subjects receiving PBO (23%) (p=0.0200, p=0.0002, p<.0001, respectively). The incidence of adverse events (AE) was similar among treatment groups and PBO: most common AEs (≥ 3%) were abdominal pain (6.0% PBO, 6.8% all MNTX), nausea (5.5%, 4.7%), flatulence (4.5%, 4.0%) and diarrhea (2.0%, 3.3%). Conclusions: Oral MNTX 150, 300 and 450mg QD significantly increased the proportion of RFBMs and decreased time to first RFBM in a dose-dependent manner in patients with OIC. Efficacy of oral MNTX in this study was comparable to that reported in clinical studies of SC MNTX in subjects with chronic, noncancer pain.
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Doxycycline-Induced Histone 2B (H2B)-Green Fluorescent Protein (GFP)Retaining Putative Stem Cells Participate in Small Intestinal Regeneration, but are Absent in the Colon Kevin R. Hughes, Ricardo Gândara, Tanvi Javkar, Fred Sablitzky, Hanno Hock, Christopher Potten, Yashwant R. Mahida
Induction Therapy for Ulcerative Colitis: Results of GEMINI I, a Randomized, Placebo-Controlled, Double-Blind, Multicenter Phase 3 Trial B.G. Feagan, P.J. Rutgeerts, B.E. Sands, J. Colombel, W.J. Sandborn, J. Colombel, S.B. Hanauer, G.A. Van Assche, J. Axler, H. Kim, S. Danese, I. Fox, C. Milch, S. Sankoh, T. Wyant, J. Xu, A. Parikh
Stem cells have been identified in two locations in small intestinal crypts, those intercalated between Paneth cells and another population (which retains DNA label) is located above the Paneth cell zone, at cell position (cp) 4. Because of disadvantages associated with the use of DNA label, we investigated the utility of doxycycline-induced transient transgenic expression of histone 2B (H2B)-green fluorescent protein (GFP) in TetOP-H2B-GFP mice (Nat Biotechnol. 2009;27:84-90). Methods. Following doxycycline-induced expression of H2B-GFP in all intestinal epithelial cells, retention of label was studied at varying time periods of chase, including post-irradiation. To study DNA-label retaining cells (LRCs) bromodeoxyuridine (BrdU) was administered for 7 days. Expression of GFP, BrdU, lysozyme, caspase 3 (identifies apoptotic cells) and phospho-histone H3 (phH3; expressed in mitosis) was studied by immunohistochemistry, double immunofluorescence and flow cytometry. Data are presented as mean(±SEM). Results. Over chase periods of up to 112 days, H2BGFP-retaining cells (with peak at cp4) were consistently seen above the Paneth cell zone in the small intestine (Table). After 14 and 28 day chase, there were significantly greater proportions of H2B-GFP-retaining cp4 cells than BrdU (DNA)-LRCs (BrdU: 6.4(±0.5)% & 3.8(±0.6)% vs data in Table; p<0.05). Majority of the BrdU-retaining non-Paneth cells also retained H2B-GFP after 14 day [86.7(±6.7)%] and 28 day [66.7(±16.7)%] chase. Post(4.5 h)-irradiation, 26.1(±11.5)% (1 Gy) and 34.6(±8.2)% (8 Gy) of H2B-GFP-retaining nonPaneth cells were apoptotic. Percentage of non-Paneth H2B-GFP-retaining cells expressing phH3 after 28 day chase: non-irradiated - 7.8(±1.4)%; after 12 Gy irradiation - 39.5(±6.2)% (24 h), 31.0(±7.6)% (48 h), 31.1(±5.9)% (72 h). In contrast to small intestine, no H2B-GFPretaining epithelial cells were seen in the colon from 28 day chase onwards. Conclusions.
AGA Abstracts
Aim: To assess the efficacy and safety of vedolizumab (VDZ), a gut-selective monoclonal antibody targeting the α4β7 integrin, as induction therapy in patients with moderate to severely active ulcerative colitis (UC) in whom at least one prior therapy had failed. Methods: The trial had both an induction and a maintenance phase; each phase was treated as an independent study for statistical analyses. The primary outcome of the induction phase was to determine the effect of VDZ treatment on clinical response (defined as a reduction in complete Mayo score of ≥3 points and ≥30% from baseline, along with a decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of ≤1 point) at 6 weeks. Secondary outcomes were to determine the effect of VDZ induction treatment on clinical remission (complete Mayo score of ≤2 points and no individual subscore >1 point) and mucosal healing (Mayo endoscopic subscore of ≤1 point) at 6 weeks. Patients with a Mayo score of ≥6 and an endoscopic subscore of ≥2 despite treatment with corticosteroids, purine antimetabolites, and/or TNFα antagonists were randomized 3:2 to receive either vedolizumab 300 mg IV or placebo on days 1 and 15. Results: The induction phase intent-to-treat (ITT) population comprised 374 patients (mean age 40.5 yrs; mean disease duration 6.5 yrs; mean baseline Mayo score 8.6). Of these, 225 received VDZ and 149 received placebo. A significantly greater proportion of VDZ-treated patients achieved clinical response, remission, and mucosal healing at 6 weeks, compared with placebo (Table 1). 39% of the ITT population had prior anti-TNFα failure. Clinical response and remission rates were higher in VDZ than placebo patients among both those
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943e MuDelta Treatment Improves Bowel Movement Frequency and Urgency Episodes in Patients with Diarrhea-Predominant Irritable Bowel Syndrome: Results of a Phase 2 Clinical Trial P.S. Covington, D. Andrae, S. Dove, C.W. Randall, C.W. Randall, J. Davenport, G. McIntyre, J. Almenoff Introduction: Simultaneously targeting mu and delta opioid receptors in the gastrointestinal tract may provide symptom relief for sufferers of diarrhea-predominant irritable bowel syndrome (IBS-d) without the constipating effects of a pure mu opioid agonist. We completed a double-blind, placebo-controlled, Phase 2 study of a minimally-absorbed, mu opioid agonist/delta opioid antagonist (MuDelta) within which we recruited patients meeting the Rome III criteria for IBS-d. Efficacy from this trial as measured by a composite outcome of stool consistency and pain measures have been previously reported and here outcomes related to patient-reported daily number of bowel movements (BMs) and urgency episodes (UEs) are presented. Methods: A total of 807 patients with IBS-d were enrolled and randomized to twice daily treatment with placebo or MuDelta doses of 5, 25, 100, or 200 mg for 12 weeks (approximately 84 days). Patients rated their BMs, UEs and other symptoms via daily diary calls to an interactive voice response system. Analyses of patients’ BM and UE frequencies were conducted via fitting longitudinal generalized linear mixed effects models to account for repeated reports by each patient. Fixed effects fit included treatment, study day, baseline average daily BM/UE values, the treatment by study day interaction, quadratic and cubic effects for study day, and the treatment by quadratic interaction for study day. A random effect was also fit to account for the repeated measurements of individuals. Higher-order time effects were fit to account for nonlinearity observed in the data over time. Estimates of BM and UE frequency as well as relative risk (RR) were computed at 28, 56, and 84 days post-baseline. Results: Summary results of the analyses are presented in Table 1. Of the total enrolled, 754 patients met the predefined intention-to-treat definition and their data were fit with the statistical models. Comparing 100 mg of MuDelta to placebo, mean BM frequency was shown to be consistently less for the 100 mg group over the course of 28 days (RR=0.90, p=.032), and significantly less over 56 days (RR=0.91, p=.042), and 84 days (RR=0.85, p= .002) of treatment. Mean UE frequency results decreased significantly for the 100 mg group over placebo at 28 days (RR=0.77, p=.021), 56 days (RR=0.79, p=.032), and 84 days (RR= 0.75, p=.012). Further, 200 mg also showed significant results for BM & EU frequency at 28 days (RR=0.81, p<.001 & RR=0.69, p<.001), 56 days (RR=0.84, p<.001& RR=0.73, p= .005), and 84 days (RR=0.87, p<.001 & RR=0.79, p=.050) as compared to placebo, respectively. Conclusion: These results indicate that MuDelta provides statistically significant and clinically meaningful efficacy in improving bowel frequency and urgency in patients with IBS-d. Research funding was provided by Furiex Pharmaceuticals.
943c ACCELERATED STEP-CARE THERAPY WITH EARLY AZATHIOPRINE (AZA) VS. CONVENTIONAL STEP-CARE THERAPY IN CROHN’S DISEASE. A RANDOMIZED STUDY. J. Cosnes, A. Bourrier, Y. Bouhnik, D. Laharie, S. Nahon, J. Bonnet, G. Getaid, F. Carbonnel, J. Dupas, R. Jean Marie, P. Jouet, G. Savoye, J. Mary, J. Colombel In early Crohn’s disease (CD) patients at risk for disabling disease, two possible treatment strategies are considered as potentially highly effective : accelerated step-care (steroids + AZA) or early combined immunosuppression (anti-TNF + AZA). However the accelerated step-care strategy (early AZA) has been poorly explored. The aim of this randomized, openlabel, controlled trial was to compare an early AZA approach with conventional step-care therapy in early CD. Methods: patients with a diagnosis of CD of less than 6mos, naive to immunosuppressors and biologics, with no previous history of surgery and having at least two predictors of disabling disease were randomized to receive AZA 2.5mg/kg at inclusion (e-AZA) or on demand according to guidelines (Controls). Predictors of disabling CD included an age<40 years, active perianal disease within the first 6 mos and need for oral steroids within the first 3 mos1. Patients were included in 24 GETAID centres between 2005, July, and 2010, December. The primary endpoint was the proportion of trimesters spent in steroid-free and anti-TNF-free remission during the first 3 years after inclusion. Data were compared between e-AZA and Control groups using non-parametric tests. Results: 147 patients were randomized to e-AZA or to Controls. Five patients were excluded just after inclusion, leaving 142 patients (71 e-AZA, 71 Controls) with a median (IQR) follow-up of 35 mos (15-36) at the reference date of on-going follow-up (2011, October 1). They were 71 M and 71 F with median age (IQR) of 27 yrs (22-29) and a median disease duration of 2.5 months (1-3.7). 42 Controls (62%) required immunosuppressors during follow-up after a median time of 5.6 months (3.2-9.6). The proportion of trimesters in remission (median, IQR) was 61% (12-83) in e-AZA patients, vs. 50% (30-72) in Controls (NS). Additionally, 19 e-AZA patients (29%) required anti-TNF vs.18 Controls (26%, NS), 2 (3%) had unplanned surgical perianal procedures vs. 9 Controls (13%, p 0.055), and 7 (11%) had intestinal surgery vs. 14 Controls (21%, p 0.11). Median values of mean CDAI and C-reactive protein did not differ between the 2 groups. Conclusion: in patients at risk for disabling CD, early AZA was not associated with a significantly increased clinical remission rate during the first years of CD. More than one third of control patients had a mild-to-moderate course not requiring immunosuppressors at a 3 year follow-up. These data do not support the widespread use of an accelerated stepcare strategy compared to conventional step-care. 1 Beaugerie et al. Gastroenterology 2006; 130: 650-6
943f TMC435 in HCV Genotype 1 Patients Who Have Failed Previous Pegylated Interferon/Ribavirin Treatment: Final SVR24 Results of The ASPIRE Trial F. Poordad, S. Zeuzem, T. Berg, E. Gane, P. Ferenci, G. Foster, M.W. Fried, C. Hezode, G. Hirschfield, I.M. Jacobson, I. Nikitin, P.J. Pockros, O. Lenz, M. Peeters, V. Sekar, G. De Smedt, M. Beumont-Mauviel
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Purpose: ASPIRE (TMC435-C206; NCT00980330) was an international, Phase IIb, randomized, double-blind, placebo-controlled trial investigating the efficacy, tolerability, safety and pharmacokinetics of TMC435 (an oral, once-daily, investigational HCV NS3/4A protease inhibitor) administered with peginterferon/ribavirin (P/R). Here we report the final SVR24 results of the ASPIRE trial. Methods: Patients were chronically-infected with HCV genotype 1, with documented evidence of null-response (<2 log10 reduction Week 12), partial response (≥2 log10 reduction Week 12; detectable end-of-treatment) or relapse (undetectable end of treatment; detectable within 24 weeks post-treatment) following ≥1 course of P/R therapy. Patients were randomized to one of seven treatment arms: TMC435 (100 or 150mg once-daily) for 12, 24 or 48 weeks in combination with 48 weeks of P/R, or placebo with P/R for 48 weeks. Results: Of 462 patients enrolled, 19% had metavir score F3 and 18% F4, 41% were infected with genotype 1a and 58% 1b. Overall, in TMC435-treated patients SVR24 rates were higher (61-80%; Table) compared with control (23%), and in F4 prior null-responders were 3146% (control 0%). In TMC435 groups, discontinuation due to viral breakthrough or lack of on-treatment response was 9-17% (control 53%), and viral relapse occurred in 6-18% (control 44%). Incidence of adverse events leading to treatment discontinuation and serious adverse events was similar across all groups. Mild, transient, asymptomatic bilirubin increases were observed with TMC435, with no significant differences between 100mg and 150mg doses. Conclusions: Following treatment with TMC435 plus P/R, patients who failed previous P/ R treatment exhibited significantly higher SVR24 rates compared with placebo, including difficult-to-treat prior null-responders with cirrhosis. TMC435 was well tolerated in this population.
A Phase 2/3 Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Subcutaneous Golimumab Induction Therapy in Patients with Moderately to Severely Active Ulcerative Colitis: PURSUIT SC W.J. Sandborn, B.G. Feagan, C.W. Marano, R. Strauss, J. Johanns, H. Zhang, J. Colombel, W. Reinisch, P. Gibson, J. Collins, G.A. Jarnerot, P.J. Rutgeerts Objective: To evaluate the safety and efficacy of subcutaneous (SC) golimumab (GLM) induction therapy in patients with moderately to severely active ulcerative colitis (UC) despite current adequate treatment or who had previously failed to respond to or tolerate treatment with 6-MP, AZA, corticosteroids and/or 5-ASAs or were corticosteroid dependent and were naïve to anti-TNF therapy. Methods: PURSUIT SC had an adaptive design with Phase 2 dose ranging followed by a confirmatory Phase 3 component. Patients with Mayo scores of 6-12 inclusive, including endoscopic subscore ≥2 were randomized to receive placebo(PBO)/PBO; GLM 100mg/50mg (before dose selection only); GLM 200mg/100mg; GLM 400mg/ 200mg at wks 0 and 2. The primary endpoint was clinical response at wk6 in patients enrolled after dose selection. Secondary endpoints at wk6 were clinical remission, mucosal healing, and change from baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ). The primary analysis population for efficacy consisted of patients randomized after dose selection (n=774); for safety, all treated patients in Phase 2 and Phase 3 were combined (n=1065). Results: 774 patients were randomized to treatment in the primary analysis population; 759 patients (98%) completed through wk6. Baseline demographics, UC disease characteristics and concomitant UC medications were similar among treatment groups. Significantly higher proportions of patients who received GLM were in clinical response, clinical remission, mucosal healing and showed improvement in the IBDQ at wk6 compared to PBO-treated patients (Table). Through wk6, the proportions of patients with AEs were similar for the combined GLM and placebo groups (39.1% and 38.2%, respectively); 3.0% and 6.1% of patients, respectively, had a serious AE. Similar rates were observed in the GLM200/100mg and GLM400/200mg groups. A death occurred in a patient in the GLM400mg/200 mg group; a single case of demyelination was reported for a patient in this group. Injection site reactions were uncommon and comparable across GLM groups. Malignancy rates were 0.3%. 0.0%, and 0.3% in the PBO, GLM200mg/100mg, and GLM400/200mg groups, respectively. Conclusion Induction regimens of SC GLM induced clinical response, clinical remission, mucosal healing and improved quality of life in anti-TNF naïve patients with moderately to severely active UC, who have had an inadequate response to conventional UC medication. The safety of GLM induction in UC was consistent with the safety profile of GLM in labeled rheumatologic indications and other anti-TNFs.
944 Transient Elastography as a Tool to Look for Total Parenteral NutritionInduced Liver Complications Myriam Dumas-Campagna, Louise D'Aoust, Michel Lemoyne, Catherine Vincent Introduction: Intrahepatic cholestasis is a potential complication of long-term total parenteral nutrition (TPN), which can progress to fibrosis. Transient elastography is a non-invasive procedure that evaluates liver fibrosis through measurement of liver stiffness. Our aim was to evaluate the feasibility and the biochemical correlations of transient elastography in a population of patients on chronic TPN. Methods: Transient elastography was performed in long-term TPN patients during their follow-up at Hôpital Saint-Luc du CHUM (Centre
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AGA Abstracts
AGA Abstracts
with prior anti-TNF failure and those with no prior anti-TNF exposure (Table 2). In preliminary analyses through week 6, rates of adverse events (AEs), serious AEs, and serious infectious AEs were similar between VDZ and placebo groups. Conclusions: Induction therapy with VDZ was significantly more effective than placebo in achieving clinical response, clinical remission, and mucosal healing in a population of UC patients with a high rate of prior anti-TNF failure. Similar rates of AEs were observed in the VDZ and placebo groups.