Baseline Stool Frequency Research Articles

P0691 Impact of Ozanimod (OZA) on Circulating Neutrophils: Results from the Phase 3 Japanese True North (J-TN) Study of Patients (Pts) With Moderately to Severely Active Ulcerative Colitis (UC)

Abstract Background OZA was approved for treatment (tx) of moderately to severely active UC in adults based on TN study results. Increases in circulating neutrophils are an indicator of systemic inflammation, and increased infiltration of activated neutrophils in intestinal mucosa contributes to mucosal inflammation in inflammatory bowel disease (IBD). Human neutrophil elastase-mediated degradation of calprotectin (CPa9-HNE) is a measure of neutrophil activity. Methods The effect of OZA on neutrophils and CPa9-HNE levels and the association of neutrophils and CPa9-HNE levels with OZA efficacy were assessed in all J-TN pts. During the 12-wk induction period, pts were randomized to OZA 0.46 mg, OZA 0.92 mg or placebo (PBO). OZA clinical responders at Week (W) 12 were continually assigned treatment to OZA or PBO for maintenance through W52. Circulating neutrophil and CPa9-HNE levels were analyzed at baseline and throughout the induction periods. Neutrophil and CPa9-HNE levels were explored by clinical response status at W12 and W52. Results Absolute neutrophil counts remained within the normal range throughout the induction and maintenance periods. Circulating neutrophil levels decreased with OZA 0.46 mg and 0.92 mg during induction and were significantly lower than those observed with PBO. Neutrophil levels significantly decreased by 2 weeks of treatment with OZA at 0.92mg dose groups compared to baseline. Circulating neutrophils remained low with continued OZA during induction period. Decreases in circulating neutrophil levels were greater in patients with clinical response starting at Week 9 (responders) than those without clinical response at Week 12 (nonresponders) in both dose Oza-treated pts groups during the induction period. CPa9-HNE levels also decreased with OZA 0.92 mg during induction period as compared with PBO and baseline. However, No significant difference of circulating Cpa9-HNE levels between responder vs nonresponser with Oza treatment at week 12. Baseline NEUT was positively associated with baseline stool frequency, 9-point Mayo and CRP. Baseline Cpa9-HNE levels was positively associate with baseline CRP. Furthermore, CfB NEUT was positively associated with CfB Physician Global Assessment, Rectal Bleeding and CRP with Oza 0.92mg treatment at week 12. CfB NEUT and Cpa9-HNE was positively associated with CfB CRP with both dose Oza treatments at week 12. Conclusion Circulating inflammatory markers of neutrophils and CPa9-HNE decreased with ozanimod use. These findings support the use of circulating neutrophils and CPa9-HNE, a measure of neutrophil activity, as pharmacodynamic markers for ozanimod treatment effect and potential disease markers in patients with UC.

P509 Upadacitinib improves symptomatic responses in patients with moderately to severely active Crohn’s disease

Abstract Background Upadacitinib (UPA), an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD), has demonstrated the ability to provide rapid symptom relief within the first week of induction treatment in patients with CD.1 As symptomatic remission is critical for patients, this phase 3 post hoc analysis evaluated the impact of UPA on patient-reported outcomes (PROs) of abdominal pain score (APS) and stool frequency (SF) over the full induction and maintenance time periods. Methods Data were pooled from the U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) induction studies evaluating patients with moderately to severely active CD with an average daily APS ≥ 2 and/or SF ≥ 4 and received UPA 45 mg (UPA45) once daily (QD) or PBO for 12 weeks. Patients who achieved clinical response to 12 weeks of UPA45 induction were re-randomised in a maintenance study (U-ENDURE, NCT03345823) to receive UPA 15 mg (UPA15) QD, UPA 30 mg (UPA30) QD, or PBO for 52 weeks. APS and SF were recorded in a daily diary and evaluated over time. Results The average daily APS (mean: PBO 1.9, UPA45 1.9) and SF (mean: PBO 5.6, UPA45 5.4), were similar between the treatment groups at induction baseline (BL). Of patients reporting BL APS ≥ 1 (PBO 91.6%, UPA45 92.4%) or BL SF ≥ 2.8 (PBO 85.6%, UPA45 85.2%), higher proportions of patients receiving UPA vs PBO achieved APS = 0 or SF ≤ 1, or complete resolution of symptoms (APS = 0 and SF ≤ 1) at week 12 of induction, as well as at week 52 of maintenance (all P ≤ .001; Figure 1A). During induction, the mean change from BL in APS and SF was improved with UPA45 vs PBO starting at week 2 through to week 12 (all P < .001; Figure 1B-C). Throughout the 52-week maintenance period, a higher proportion of patients receiving UPA15 or UPA30 achieved APS ≤ 1 or SF ≤2.8 vs PBO (Figure 1B-C). Patients treated with UPA30 demonstrated a numerically higher rate of symptomatic response vs UPA15. In patients who met the Crohn's Disease Activity Index (CDAI) criteria per US labeling (CDAI ≥ 220 at induction BL; clinical response [CR-100] at week 12 with UPA45),2 comparable symptom improvements were observed over time compared to the overall study population. Conclusion Patients with moderately to severely active CD demonstrated improvements in APS and SF as early as 2 weeks after UPA induction treatment. A greater proportion of patients achieved PRO-defined remission within 12 weeks of UPA induction treatment compared with PBO, which were sustained through week 52 of UPA maintenance treatment.

Comparison of Glucose ORS with and without Rice Based ORS in Treatment of Acute Gastroenteritis from 6 Month to 5 Years

Introduction: Acute gastroenteritis-related diarrhea is a major contributor to pediatric morbidity and mortality. Although the success of various oral rehydration formulations varies and the treatment of choice ultimately depends on the underlying reason, oral rehydration remains crucial for efficient early therapies. Objective: To compare outcome of Glucose ORS with and without rice based ORS in treatment of acute gastroenteritis from 6 month to 5 years in terms of mean stool frequency. Study Design: Randomized clinical trial Settings: The study will be done at department of Peads Ittifaq Hospital Lahore from 9 December 2018 to 19 June 2019. Sample Technique: Non probability consecutive sampling Methodology: Children of both sexes were included in this analysis of gastroenteritis cases between the ages of 6 months and 5 years. They divided into two separate groups. For 48 hours, group A was given G-ORS, whereas group B was given rice soup. Over the course of 48 hours, the typical individual needs to use the washroom. Results: Eighty people took part in the study (forty in each group). There were 25 males in Group A (40.02%), and 26 in Group B (50.98%). The average ages of those in Group A and Group B were very comparable (3.30±1.18 vs. 2.07±1.03 years, p=0.29). The baseline stool frequency of Group A was 4.11±2.33, while that of Group B was 5.01±2.81 (p= 0.51). Group A also had a higher mean weight, at 6.87±1.97, than Group B, at 6.28±2.01. Group A had an average of 2.15±0.77 bowel movements in 48 hours, while Group B had an average of 2.08±0.73 (p=0.91). The mean frequency was 2.170.78 for males, 2.14±0.69 for females, and 2.11±0.72 for both sexes combined (p=0.91). There were no statistically significant differences in age, BMI over 10, or baseline frequency. Practical implication: The purpose of this research was to more exactly explain the authentic benefit of rice-based ORS in comparison to glucose ORS and to evaluate whether or not there is significant differences. Conclusion: Both groups reduced the number of incidences of the confounding variable roughly at the same rate, and there was no statistically significant difference between them either in terms of that reduction or in terms of stratification of any of the study's other confounding variables. Keywords: G-ORS, Gastroenteritis, Stool frequency, Rice soup

S761 Association Between Absolute Lymphocyte Count and Ozanimod Efficacy/Safety in Patients With Moderate/Severe Ulcerative Colitis: Results From the Phase 3 True North Study

Introduction: Ozanimod (OZA) is approved in the USA and EU for treatment (tx) of moderate/severe UC. OZA binding internalizes S1P1 receptors, reducing egress of lymphocyte subsets into circulation. OZA was approved in this patient (pt) population based on results of the phase 3 True North (TN) study (NCT02435992). Methods: We evaluated association between absolute lymphocyte count (ALC) and OZA efficacy/safety during TN’s induction period (IP) and maintenance period (MP). Pts were randomized to double-blind (DB) OZA 0.92 mg or placebo (PBO) or open-label (OL) OZA during 10-week (W) IP. Pts with clinical response to OZA at W10 were rerandomized to DB OZA or PBO for MP through W52. Rectal bleeding (RB), stool frequency (SF), composite Mayo, Physician’s Global Assessment (PGA), and endoscopy scores were assessed at baseline and as clinical outcomes at W10 and W52. Efficacy endpoints (EPs; clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission) were assessed at W10 and W52. Tx-emergent adverse events (TEAEs) and ALC were evaluated at baseline and W5, W10, W18, W28, W40, and W52. Results: During IP, 645 pts received DB OZA (n=429) or PBO (n=216) and 367 received OL OZA; for MP, 230 and 227 OZA-treated pts were rerandomized to OZA and PBO, respectively. Baseline ALC was not significantly correlated with clinical outcome at W10 or W52 as measured by changes from baseline RB, SF, Mayo, PGA, and endoscopy scores in pts on OZA or PBO. Baseline ALC was not predictive or prognostic for W10 and W52 responses based on the efficacy EPs. Reductions from baseline in mean ALC occurred by W5 with OZA and were significantly greater with OZA (53-54%) vs PBO (2.3%; P< .001). ALC plateaued by W10 and was maintained through W52 in pts on continuous OZA. ALC returned to PBO levels by W52 in pts who switched to PBO during MP. Change in ALC at W10 was generally not significantly correlated with changes in clinical outcomes at W10 or W52. Change in ALC at W5 was not predictive of W10 response; change in ALC at W10 was not predictive of W52 response. Reductions from baseline in ALC at all weeks were similar in OZA-treated pts with/without ≥1 TEAE and with/without infection TEAEs. Conclusion: ALC reductions occurring with OZA were reversed upon tx discontinuation and were not associated with TEAEs. Baseline ALC and ALC reductions were not predictive or prognostic for response. These findings support ALC as a pharmacodynamic biomarker but not as a prognostic or predictive biomarker.

Oral beclomethasone dipropionate is an effective treatment for immune checkpoint inhibitor induced colitis

IntroductionSystemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD)...

DOP86 Mirikizumab-induced upregulation of colonic transcripts correlates with improvements in stool frequency in a phase 2 study of patients with moderately to severely active Ulcerative Colitis

Abstract Background We have previously shown that treatment with mirikizumab (miri), a p19-directed IL-23 antibody, significantly downregulates inflammatory genes associated with disease activity and upregulates genes expressing epithelial transporter proteins in colonic tissue in patients with ulcerative colitis (UC). Here we explored the correlation between the expression of colonic mucosa genes and stool frequency (SF), a symptom reflective of disease activity, during the 12-week induction period of a Phase 2 study of patients with moderately to severely active UC (NCT02589665). Methods Patients were randomised 1:1:1:1 to receive intravenous placebo (PBO), miri 50mg or 200mg with possibility of exposure-based dose increases, or fixed miri 600mg every 4 weeks for 12 weeks. SF was reported daily by patients and transformed on a 4-level ordinal scale [0–3] representing increased SF above their normal or healthy baseline (BL). Patient colonic biopsies (PBO N=58, miri 50mg N=52, 200mg N=51, 600mg N=54) were collected at BL and Week (W)12, and gene expression measured using an Affymetrix HTA2.0 microarray workflow. BL and W12 gene expression or SF values were pooled and associations identified based on non-parametric Kendall’s tau. Pathway analysis (Hallmark and Reactome) of correlated genes was performed using over-representation analysis. p values of enrichment were determined by hypergeometric distribution test and adjusted for multi-testing with Benjamini-Hochberg procedure. Differential gene expression after miri treatment was determined by paired t-test comparing expression levels at BL and at W12 using data from the 200mg treatment group. Results A total of 267 genes were correlated with SF (|tau| &amp;gt;0.3 and qval &amp;lt;0.001). Of these, 212 were positively correlated (high expression associated with high SF) and 55 were negatively correlated (high expression associated with low SF). The 212 transcripts that were positively correlated with SF were uniformly and consistently downregulated with miri treatment, while the 55 transcripts that negatively correlated with SF, were consistently upregulated with miri treatment (Table 1). Biological pathways significantly associated with the miri-responsive transcripts that correlated with SF included inflammatory response, extracellular matrix dysregulation, neutrophil degranulation and cytokine signaling pathways, especially TNF and IL6 pathways (Table 2). Conclusion This is the first study to identify colon-based transcripts that correlate with a clinical disease activity measure, stool frequency, and it demonstrates that treatment with miri may upregulate genes associated with normalization of SF and down regulate genes associated with inflammation in colonic tissue samples of patients with UC.

DOP84 Early treatment responses within 14 days of intravenous vedolizumab induction therapy for Crohn’s Disease: Post hoc analysis of patient-reported outcomes from the VISIBLE 2 study

Abstract Background Vedolizumab (VDZ), an anti-a4β7 integrin antibody that selectively blocks lymphocyte trafficking to the gut, is approved for the treatment of adult patients with moderate-to-severe Crohn’s disease (CD). This post hoc analysis of data from the VISIBLE 2 trial evaluated early patient-reported outcomes assessed within the first 14 days of VDZ induction. Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a phase 3, multicentre, placebo-controlled study, evaluating the efficacy and safety of subcutaneous VDZ for maintenance treatment in patients with moderately to severely active CD. Efficacy was assessed based on CD Activity Index (CDAI). Patients received induction treatment with intravenous (IV) VDZ 300 mg open-label at Weeks 0 and 2. For this analysis, responses to VDZ were assessed using CDAI sub-scores for patient-reported abdominal pain (AP) and stool frequency (SF) collected daily via electronic diary in the first 14 days of VDZ treatment (Day 1 to 15) in all patients receiving ≥1 VDZ dose at induction. Descriptive statistics were used. Results The analysis included 611 patients (mean [SD] age 37.6 [13.4] years; CD duration 9.0 [8.1] years); 323 (53%) were male; 228 (37%) had severe disease (CDAI &amp;gt;330) at baseline; and 350 (57%) were anti-TNF-experienced. In the first 14 days of VDZ IV induction, the rate of patients with daily SF≤3 increased from 30% at baseline (Day 1) to 47.7% on Day 15. Increases were similar in both anti-TNF-naïve vs. anti-TNF-experienced patients and in patients with severe vs. moderate disease (Figure 1). Mean baseline SF was reduced from 6.4 to 5.0 at Day 15 in patients with severe disease and from 4.3 to 3.5 in patients with moderate disease. Overall, the proportion of patients rating AP as severe/moderate declined from baseline to Day 15 of induction (from 14.6% to 8.2% for severe AP and from 60.7% to 40.6% for moderate AP). Similar Day 1-to-15 reductions were reported in both anti-TNF-naïve (severe AP: 14.2% to 9.2%; moderate AP: 62.6% to 44.6%) and anti-TNF-experienced patients (severe AP: 14.8% to 7.4%; moderate AP: 59.3% to 37.7%), respectively. Although a minority of patients (6.3%) in the sub-group with moderate AP at baseline had worse pain at Day 15, there were early improvements in AP ratings for most patients reporting severe or moderate AP at baseline (Figure 2). Conclusion This post hoc analysis of daily patient-reported SF and AP in the VISIBLE 2 CD study indicates an early onset of response to VDZ IV induction within the first 14 days of treatment.

Week 2 Symptomatic Response with Vedolizumab as a Predictive Factor in Japanese Anti-TNFα-Naive Patients with Ulcerative Colitis: A post hoc Analysis of a Randomized, Placebo-Controlled Phase 3 Trial

Background and Aim: To evaluate the onset of symptomatic response with vedolizumab in patients with moderate-to-severe ulcerative colitis in Japan. Methods: Patients were randomized to receive vedolizumab 300 mg or placebo at Weeks 0, 2, and 6. Mayo subscores were analyzed in patients with baseline stool frequency (SF) ≥1 and rectal bleeding (RB) ≥1. In patients with baseline SF ≥2 and RB ≥1, the proportion who achieved SF ≤1 and RB = 0 was determined. Results: Patients were randomized to vedolizumab (n = 164) or placebo (n = 82). Decrease from baseline in mean SF subscore was greater with vedolizumab versus placebo from Week 2 (−6.6%; 95% confidence interval [CI], −16.2, 3.0), with a greater difference in anti-tumor necrosis factor (TNF)α-naive patients (vedolizumab vs. placebo, −13.2%; 95% CI, −29.7, 3.3). Mean percentage decrease from baseline RB subscore was numerically greater with vedolizumab versus placebo from Week 6 in anti-TNFα-naive patients (−10.7%; 95% CI, −33.0, 11.5). More patients in the anti-TNFα-naive subgroup achieved SF ≤1 and RB = 0 with vedolizumab versus placebo at Week 2 (14.8%; 95% CI, 2.5, 27.0) and Week 6 (20.3%; 95% CI, 4.4, 36.2). Patients with SF ≤1 and RB = 0 at Week 2 had higher clinical response, clinical remission, and mucosal healing rates at Week 10 than those without. Conclusions: Our results indicate that vedolizumab induces a rapid symptomatic response, particularly in anti-TNFα-naive patients, and suggest that early symptomatic improvement predicts treatment response at Week 10 (NCT02039505).

Predictive factors for achievement of mucosal healing by budesonide 2-mg foam in ulcerative colitis: a pooled analysis of data from two clinical trials.

Background/AimsMucosal healing (MH) of distal lesions in ulcerative colitis (UC) has recently been confirmed with budesonide 2-mg foam (BF) treatment in 2 clinical trials; however, few studies have investigated the predictive factors for complete MH.MethodsWe conducted a post hoc analysis using pooled data from phase II and III clinical trials evaluating the efficacy and safety of BF for UC. Additionally, we analyzed the relationships between complete MH and baseline factors and clinical symptoms from baseline to week 6.ResultsAmong the 291 Japanese patients from the 2 pooled clinical studies, 119 patients in the BF twice a day group and 117 in the placebo group were included in the full analysis set. The proportion of patients with a rectal bleeding (RB) subscore of 0 was significantly higher in the BF group than in the placebo group after a 5-day treatment (P<0.05). After a 2-day treatment, significantly more patients in the BF group had a stool frequency (SF) subscore of 0 than patients in the placebo group (P<0.05). Multivariate analysis showed that complete MH at week 6 was influenced by baseline SF subscore and 5-aminosalicylic acid (5-ASA) enema or suppository use (P=0.0086 and P=0.0015, respectively). The relationship between complete MH at week 6 and RB subscore after week 2 was also confirmed.ConclusionsNormal SF at baseline, history of 5-ASA topical product use, and elimination of RB after week 2 are suggested predictors of complete MH at week 6 with twice-daily BF treatment.

834 Early Symptom Improvement With Risankizumab Treatment in Patients With Moderately to Severely Active Crohn’s Disease: Analysis From a Phase 2 Study

INTRODUCTION: Risankizumab (RZB), an IL-23 p19 inhibitor, has shown safety and efficacy in inducing clinical remission in patients with Crohn’s disease (CD) in a Phase 2 study.1 Here we assessed early symptom improvement during the randomized, double-blind, placebo-controlled induction phase of the trial. METHODS: This Phase 2 study enrolled adult patients with moderate-to-severe CD with a Crohn’s Disease Activity Index (CDAI) of 220–450, ulcers in the ileum and/or colon, and a Crohn’s Disease Endoscopic Index of Severity (CDEIS) ≥7 (≥4 for patients with isolated ileitis) assessed by ileocolonoscopy confirmed by a blinded central reader. Patients were randomized 1:1:1 to receive intravenous RZB (200 mg or 600 mg) or placebo at Weeks 0, 4, and 8. Endpoints examined in this post hoc analysis included changes from baseline at Weeks 2, 4, 8, and 12 in CDAI, average daily stool frequency (SF) and average daily abdominal pain score (AP) for all patients with available data, and newly defined clinical remission at Week 12, based on symptom improvement, defined as SF ≤ 2.8 and AP ≤1, both not worse than baseline, in patients with baseline SF ≥ 4 or AP ≥2. Continuous endpoints were analyzed using observed case; non-responder imputation was used for missing data of binary endpoints. Statistical comparisons of median change were based on Wilcoxon rank sum test. RESULTS: 121 patients were randomized in the induction phase. Baseline characteristics were similar among treatment arms.1 Mean (SD) disease duration at baseline was 13.4 (9.4) years; 94.2% of patients received previous anti-TNF therapy. Significant improvements in CDAI and AP were observed with RZB (600 mg) versus placebo as early as Week 2 and in SF at Week 8 (Table 1). The proportion of patients with clinical remission based on symptom improvement was significantly higher in the 600 mg RZB group versus placebo at Week 12 (23.7% versus 6.1%; P &lt; 0.05), supporting the previously reported superiority of RZB versus placebo for inducing CDAI remission at Week 12 (36.6% of 600 mg RZB versus 15% of placebo; P &lt; 0.05). CONCLUSION: RZB induction treatment was associated with significant early improvements in clinical symptoms and disease activity in a highly refractory patient population with moderately to severely active CD.

Deep Remission With Vedolizumab in Patients With Moderately to Severely Active Ulcerative Colitis: A GEMINI 1 post hoc Analysis.

Background and AimsThis GEMINI 1 post hoc analysis evaluated vedolizumab efficacy for inducing deep remission in patients with ulcerative colitis and correlation between vedolizumab trough concentrations and deep remission rates.MethodsWeek 6 vedolizumab responders were re-randomized to placebo or vedolizumab every 8 or 4 weeks. Deep remission at Week 52 was measured using four different definitions [from most to least stringent]: [1] Mayo Clinic endoscopic score = 0, rectal bleeding score = 0 and decrease or no change from baseline in stool frequency score; [2] endoscopic score ≤1, rectal bleeding score = 0 and stool frequency score = 0; [3] endoscopic score ≤1, rectal bleeding score = 0, decrease or no change from baseline stool frequency score, and total score [endoscopic score + rectal bleeding score + stool frequency score] ≤1; and [4] endoscopic score ≤1, rectal bleeding score = 0 and stool frequency score ≤1. Steady-state trough vedolizumab serum concentrations were evaluated.ResultsAt Week 6, 373 vedolizumab responders were re-randomized to maintenance placebo [n = 126] or vedolizumab every 8 [n = 122] or 4 [n = 125] weeks. Significantly more vedolizumab patients achieved deep remission at Week 52 for the most (placebo 8.7%, every 8 weeks 27.0% [p = 0.0001], every 4 weeks 28.0% [p < 0.0001]) and least (placebo 15.9%, every 8 weeks 43.4% [p < 0.0001], every 4 weeks 43.2% [p < 0.0001]) stringent definitions. Patients with higher vedolizumab trough concentration quartiles had higher deep remission rates [all definitions] compared with those with the lowest quartile or who received placebo.ConclusionVedolizumab was associated with significantly higher deep remission rates than placebo at Week 52, regardless of deep remission definition [NCT00783718].

Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis

Tofacitinib is an oral, small molecule inhibitor of JAK for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post-hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2). The studies comprised patients with moderate to severe active UC who were intolerant to, orfailed by previous treatment with, corticosteroids, thiopurines, and/or tumor necrosis factor(TNF) antagonists. Patients received tofacitinib (10 mg twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo stool frequency and rectal bleeding subscores were calculated using diary data from the first 15 days of therapy. We analyzed data from subgroups including failure of prior anti-TNF therapy, baseline corticosteroid use, and baseline serum levels of C-reactive protein. Mean changes were significantly greater in patients given tofacitinib vs placebo in reductions from baseline stool frequency subscore (tofacitinib: -0.27 vs placebo: -0.11; P < .01), total number of daily bowel movements (-1.06 vs -0.27; P < .0001), and rectal bleeding subscore (-0.30 vs -0.14; P < .01) by day 3. Compared with placebo, more tofacitinib-treated patients had reductions from baseline in stool frequency subscore (by ≥1 point for tofacitinib, 241/837, 28.8% vs placebo, 39/218, 17.9%) (P < .01) and rectal bleeding subscore (by ≥1 point for tofacitinib, 266/830, 32.0% vs placebo, 43/214, 20.1%) (P < .01) by day 3. A consistent effect of tofacitinib was observed in all subgroups. In a post-hoc analysis of data from phase 3 trials of induction therapy with tofacitinib in patients with UC, we found significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days. These findings indicate the rapid onset of effect of this drug in patients with UC. ClinicalTrials.gov no: NCT01465763 and NCT01458951.

Performance of Crohn's disease Clinical Trial Endpoints based upon Different Cutoffs for Patient Reported Outcomes or Endoscopic Activity: Analysis of EXTEND Data.

Clinical trial endpoints for Crohn's disease (CD) activity correlate poorly with mucosal inflammation; to assess treatment efficacy, patient-reported outcomes and endoscopic assessments are preferred. This study assessed the impact on treatment efficacy estimations of using different definitions of clinical and endoscopic remission and endoscopic response, and of using site- or central-based endoscopy evaluation. This post hoc analysis of data fromEXTEND (extend the safety and efficacy of adalimumab through endoscopic healing), a placebo (PBO)-controlled, randomized trial of adalimumab (ADA) for mucosal healing, included adults with moderate-to-severe CD. Subsets of patients meeting specified Simplified Endoscopic Score for CD (SES-CD) inclusion criteria, according to site or central reading, and baseline stool frequency (SF) and/or abdominal pain score (AP) thresholds were evaluated. Various endpoint definitions based on the Crohn's Disease Activity Index (CDAI), its SF and AP components, SES-CD, and composite endpoints were compared between treatment groups. Increased stringency of Week 12 clinical endpoints compared to CDAI<150 to SF≤3.0/1.5&AP≤1.0 reduced PBO response rates by ≥12% and increased treatment effects by ≤10%. Amending the SES-CD endpoint from ≤4 to ≤2 reduced the treatment effect from 24% to 8%. Composite endpoints further diminished response rates and effect sizes. Site-based evaluation was associated with lower remission rates versus central reading in the PBO group and, thus, greater ADA-related treatment effects. This analysis is the first to demonstrate that increasing the stringency of clinical and endoscopic endpoint definitions in CD trials, especially lowering SF or SES-CD definitions, reduces the ability to detect treatment-related change in CD activity; focus on endpoints that reflect clinical change is warranted.

Increased PECAM-1 Predicts Increased Risk for Flare in Patients With IBD

Introduction: Predicting risk of flare-ups for patients with inflammatory bowel disease (IBD) is difficult. Changes in epithelial permeability may be an early event leading to flares in IBD. Particularly, cell adhesion molecules (CAM) are important in regulating the migration of leukocytes into the gut. We aimed to identify specific biomarkers in the colonic mucosa related to epithelial cell tight junctions that may predict the risk of relapse in a group of patients with clinically inactive inflammatory bowel disease. Methods: We identified patients with clinically inactive IBD, defined as baseline stool frequency without blood and no abdominal pain, who underwent elective colonoscopy at our VA Medical Center. Followup at 6, 12, and 24 months were reviewed to assess whether patients had relapsed or remained in remission. Relapse was defined as an increase in disease activity (i.e., increased number of stools, presence of blood, and/or abdominal pain) that the treating physician deemed as a relapse and required a change in the medication regimen. Tissue samples obtained from each patient at baseline were evaluated for gene expression by real time PCR using RT2 Profiler Human Tight Junction PCR Array (Qiagen). Results: 40 patients (23 UC, 16 Crohn's, 1 indeterminate colitis) underwent colonoscopy with tissue sampling while in clinical remission. All patients had colonic involvement of their disease; average age at enrollment 59.2 years, 88% male, 88% white, average disease duration 18 years. At 6 months from the index colonoscopy, 8 patients had experienced a flare (20%), 9 by 12 months (23%), and 11 by 24 months (28%). Preliminary analysis of 84 candidate genes was evaluated in 6 patients who experienced a flare and 6 who remained in remission. We found platelet endothelial cell adhesion molecule-1 (PECAM1) to be elevated 2.8-fold in biopsies from our patients who subsequently flared as compared to those who did not (p=0.023). Conclusion: Increased expression of PECAM1 may be an early event precipitating active inflammation in patients with IBD, particularly in UC. Looking for PECAM1 in biopsy specimens of IBD patients in clinical remission may be helpful in predicting which patients are at increased risk of flare. This may be useful in facilitating the individualization of maintenance therapy.

Su1376 Retrospective Comparison of the Efficacy of Anti-TNF Agents in Isolation or Combined With Azathioprine in Prevention of Early Postoperative Endoscopic Recurrence in Crohn's Disease From the Multiper Database

collagenous band thickness, and lamina propria inflammation. Hazard ratios (HR) were calculated by logistic regression analysis with 95% confidence intervals. Results: The overall symptom relapse rate was 61%. By multivariate analysis, a baseline stool frequency >5/day (HR 3.95; 1.08 14.39), a history of diarrhea >12 months (HR 1.77; 1.04 3.03), and the absence of budesonide maintenance therapy (HR 2.71; 1.37 5.38) were associated with symptom relapse. The time to relapse was shorter in patients with a baseline stool frequency >5/day (56 vs. 199 days, p = 0.024), as in those with a history of diarrhea >12 months (56 vs. 220 days, p = 0.009). Budesonide maintenance therapy delayed the time to relapse (56 versus 207 days, p = 0.005). Conclusions: Our data demonstrate that a high stool frequency at baseline and a long duration of diarrhea are risk factors for symptom relapse in collagenous colitis, while budesonide maintenance therapy is a protective factor against symptom relapse.

Risk Factors for Symptom Relapse in Collagenous Colitis After Withdrawal of Short-term Budesonide Therapy

Oral budesonide has been proven effective in short- and long-term treatment of collagenous colitis; however, symptom relapse frequently occurs after drug withdrawal. The aim of this study was to identify the risk factors for symptom relapse in patients with collagenous colitis after withdrawal of short-term budesonide therapy. One hundred twenty-three patients from 4 randomized controlled studies who achieved clinical remission after short-term treatment with budesonide (9 mg/d) were analyzed, including 40 patients receiving subsequent budesonide maintenance therapy (6 mg/d) for 6 months and 83 patients without active maintenance treatment. Variables available for analysis were age, sex, baseline stool frequency, duration of diarrhea, collagenous band thickness, and lamina propria inflammation. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated by Cox proportional hazard model. The overall symptom relapse rate was 61%. By multivariate analysis, a baseline stool frequency >5 per day (HR, 3.95; 95% CI, 1.08-14.39), history of diarrhea >12 months (HR, 1.77; 95% CI, 1.04-3.03), and the absence of budesonide maintenance therapy (HR, 2.71; 95% CI, 1.37-5.38) were associated with symptom relapse. The time to relapse was shorter in patients with a baseline stool frequency >5 per day (56 versus 199 d, P = 0.024), as in those with history of diarrhea >12 months (56 versus 220 d, P = 0.009). Budesonide maintenance therapy delayed the time to relapse (56 versus 207 d, P = 0.005). Our data demonstrate that a high stool frequency at baseline and a long duration of diarrhea are risk factors for symptom relapse in collagenous colitis, whereas budesonide maintenance therapy is a protective factor against symptom relapse.

Electron microscopic changes in Enterocytozoon bieneusi following treatment with albendazole.

To identify and describe electron microscopic changes occurring in Enterocytozoon bieneusi in patients treated with albendazole. Eighteen HIV seropositive patients with E bieneusi infection of the small intestine were treated with albendazole 400 mg twice a day for one month. Duodenal biopsy specimens obtained before and at the end of treatment were examined electron microscopically by a pathologist who was unaware of the clinical response. A semiquantitative assessment of the parasite load and description of the parasite morphology was made. A complete resolution of diarrhoea occurred in nine patients and a further three had a greater than 50% reduction in baseline stool frequency or volume. Three of the non-responders were also infected with cryptosporidium. There was a reduction in parasite load in those responding to treatment and an increase in abnormal forms in both responders and non-responders. The clinical response to albendazole treatment seen in some patients with small intestine microsporidiosis may be due to damage to the developmental stages, causing a partial inhibition of parasite reproduction.