Sa1152 Long-Term Safety of Adalimumab in Pediatric Patients With Crohn's Disease

receiving HD ADA (27.3%) vs LD ADA (18.4%). Greater proportions of IFX-Naive patients achieved CS-free remission at wk 26 (P=0.004) compared to patients with prior IFX use (Table). At wk 26, 52.9% of IFX-Naive patients receiving HD ADA were in CS-free remission. BL disease severity did not appear to affect CS-free remission rates. Conclusion In pediatric patients with moderately to severely active CD who used CS at BL in IMAgINE 1, trends toward higher CS-free remission rates were observed with HD ADA treatment. CS-free remission rates were higher in IFX-Naive patients than in IFX-experienced patients, but were not clearly affected by BL disease severity. Reference: 1. Hyams J, et al. Gastroenterol. 2012; 143:365. Proportion of Patients Achieving CS-Free Clinical Remission

ADA=adalimumab; BL=baseline; CS=corticosteroid; HD=higher dose; IFX=infliximab; LD= lower dose; PCDAI=Pediatric Crohn's Disease Activity Index. *P value is from a logistic regression model with treatment as the only predictor. Sa1152 Long-Term Safety of Adalimumab in Pediatric Patients With Crohn's Disease Joel R. Rosh, Frank Ruemmele, Marla Dubinsky, Johanna C. Escher, Jaroslaw Kierkus, Jeffrey S. Hyams, Andreas Lazar, Samantha Eichner, Yao Li, Roopal Thakkar Background: The safety profile of adalimumab (ADA) in children enrolled in the IMAgINE 11 clinical trial and the open-label extension (OLE) has been reported up to 3 years2. A safety update, with up to 5 years of ADA exposure, is presented. Methods: Patients (pts) completing the IMAgINE 1 trial could enroll in the OLE. Adverse events (AEs) were reported from the first dose through the June 30, 2013 cut-off or up to 70 days after the last ADA dose for any pt that received at least one dose of ADA. Rates of AEs were assessed per 100 patient-years (PY). Subgroup analysis by prior infliximab (IFX) use was performed. Results: A total of 192 children have received at least one dose of ADA in IMAgINE 1 and the OLE, totaling 422.2 PY of exposure. As of June 30, 2013, 115/192 pts (59.9%), 82/192 (42.7%), 75/192 (39.1%), 58/192 (30.2%), and 15/192 (7.8%) have at least 1, 2, 3, 4, or 5 years of ADA exposure, respectively. An overview of the treatment-emergent AEs for all pts and by prior IFX use is shown in the table. The most common serious AE (SAE) was flare or worsening of CD and most (7/11) opportunistic infections were non-serious oral candidiasis. The exposure-adjusted rate of SAEs and AEs leading to discontinuation were significantly higher for IFX experienced pts than IFX Naive pts (Table). The rate of serious infections observed between pts receiving ADA with or without concomitant immunosuppressant (IMM) and/or corticosteroid (CS) use at baseline were 3.5 E/100PY ADA monotherapy, 6.2 E/100PY ADA + IMM, 4.4 E/100PY ADA + CS, and 12.5 E/100PY ADA + IMM + CS (p= 0.09). No malignancies or deaths have been reported to date. Conclusion: No new safety risks have been identified with prolonged ADA treatment in children with Crohn's disease. The safety profile of ADA in children with Crohn's disease continues to be consistent with previously published reports1,2. References: 1. Hyams JS, et al. Gastroenterol. 2012; 143:365. 2. Baldassano R, et al. Abstract presented at 21st UEG Week 2013. Treatment-emergent AEs as of 30 June 2013

Sa1151 Steroid-Free Remission in Adalimumab-Treated Pediatric Patients With Moderately to Severely Active Crohn's Disease in the IMAgINE 1 Trial Anne M. Griffiths, Wallace Crandall, Richard B. Colletti, Frank Ruemmele, William A. Faubion, Jeffrey S. Hyams, Andreas Lazar, Yao Li, Samantha Eichner, Roopal Thakkar Background The efficacy of adalimumab (ADA) in inducing and maintaining remission in pediatric patients with Crohn's disease (CD) was demonstrated in IMAgINE 1 1 (NCT00409682). This analysis further investigated corticosteroid (CS)-free remission in the subset of patients receiving CS at baseline (BL). Methods Patients aged 6-17 y with CD resistant or intolerant to conventional therapy, including infliximab (IFX), and BL Pediatric CD Activity Index (PCDAI) >30 received open-label (OL) induction of ADA at weeks (wks) 0/2 by body weight (<40 kg, 80/40 mg; ≥40 kg, 160/80 mg). At wk 4, patients were stratified by response and prior IFX use, and randomized to double-blind (DB) higher-dose (HD) ADA (<40 kg, 20 mg every other wk [eow]; ≥40 kg, 40 mg eow) or lower-dose (LD) ADA (<40 kg, 10 mg eow; ≥40 kg, 20 mg eow) for 48 wks. Patients with disease flare or nonresponse could move to DB weekly dosing after wk 12, then to OL weekly HD ADA for continued flare/nonresponse. Proportions of patients receiving LD ADA vs HD ADA achieving CS-free clinical remission (PCDAI ≤10) were compared using a logistic regression model overall, by prior IFX use, and by BL disease severity (PCDAI: <40, ≥40). Nonresponder imputation was used for missing values and patients who moved to weekly dosing. Results Of 188 patients randomized to ADA, 38 in the LD ADA group and 33 in the HD ADA group were using CS at BL. Of these, 33.3% receiving HD ADA and 26.3% receiving LD ADA achieved CS-free remission at wk 26 (P=0.519)1 (Table). CS-free remission rates at wk 52 were also numerically higher but did not reach statistical significance for patients

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AGA Abstracts

AGA Abstracts

influence CD risk, but supporting evidence is sparse and generally originates from small studies with limited follow-up. To guide future research, we sought to further evaluate the association between a number of potential risk factors during the first year of life and subsequent CD by performing a nationwide birth cohort study in Denmark. Methods: All children born in Denmark between 1995 and 2009 were identified in the Danish Medical Birth Registry and followed until death, emigration, or end of study (January 1, 2013). Cases of CD were identified using the Danish National Patient Registry (DNPR), using a validated case-finding algorithm (PPV > 90%). Multivariate cox proportional hazards models were used to identify potential risk factors associated with the development of CD. Candidate risk factors were selected a. priori and ascertained through the DNPR or the nationwide prescription database. Results: The birth cohort consisted of 979,039 children followed for a mean of 9.5 years (9,262,962 person-years of follow up). The characteristics of these children are displayed in the table. A total of 208 cases of CD were observed during followup. As expected, there was a strong association with family history of CD (HR 14.0, 95% CI 6.9,28.3) (Table). The multivariate analysis further identified urban life (HR= 1.4, 95% CI 1.0-1.8), caesarean section (HR=1.3, 95%CI 0.9-1.8), and early life antibiotic use/infections requiring hospitalization (HR=1.4, 95% CI 1.0-1.8) as potential risk factors for CD. We found no independent associations for the following factors: gender, birth order, gestational age, maternal smoking during pregnancy, birth year, and NSAID use during first year of life (Table). Discussion: In addition to the well-known association between family predisposition and risk of CD, our exploratory analysis identified factors related with changes in the host microbiome as potential risk factors for CD. These findings support the hygiene hypothesis. Table

Sa1154 The Predictive Value of Probe-Based Confocal Laser Endomicroscopy (pCLE) Findings in Pediatric Inflammatory Bowel Disease Patients Anton Shavrov, Anastasia Kharitonova, Brian Claggett, Andrey Shavrov, Julia J. Liu

AGA Abstracts

Purpose: Studies over the past two decades have convincingly demonstrated the role of barrier dysfunction in the pathogenesis of inflammatory bowel disease (IBD). The predictive value of barrier dysfunction as measured by epithelial gaps seen on pCLE for disease relapse were reported in adult IBD patients. The purpose of the current study was to determine the predictive value of pCLE findings in pediatric IBD patients. Methods: This is a prospective follow-up study of pediatric IBD, both Crohn's disease (CD) and ulcerative colitis (UC) patients who underwent pCLE during routine colonoscopy in a tertiary referral center. Primary study end-point was moderate to severe flare requiring hospitalization after pCLE. The pCLE videos were blindly reviewed by an expert confocal endoscopist for analysis of epithelial cells and gaps and scoring of adequacy of imaging. The pCLE images were scored for the following parameters: 1. number of areas sampled, 2. presence of diseased areas on pCLE images, 3. clear visualization of cells, 4. proximity to ileo-cecal valve. The epithelial gap density was calculated based on the total number of epithelial gaps normalized to the total number of epithelial cells on adequately imaged villi. The primary study end-point was moderate to severe relapse. We investigated the relationship between presence of epithelial gaps and the primary outcome and the degree to which such a relationship may depend on imaging parameters using Cox models. Results: A total of 24 IBD patients (13 CD, 11 UC) were followed for a median of 13 months (range 4 to 33). There were 13 F (54%) and 11 M (46%) with a median age of 14 yr (range 10 to 21). The median duration of disease at the time of pCLE was 2.9 yr (range 0 to 9); for therapy, 6 patients (25%) were on antiTNF agents, 8 (33%) were on 5-ASA, 2 (8%) were on steroids, 1 (4%) was on no therapy, the remaining 7 patients (29%) were on different combination regimens. The disease distributions for CD were: ileo-colitis in 9 patients (70%), ileitis in 2 (15%) and colitis 2 patients (15%). For UC: 7 patients (64%) had pan-colitis, distal colitis in 3 (27%) and proximal colitis in 1 (9%). 9 patients (38%) had moderate to severe relapse requiring hospitalization during the follow-up period. Amongst videos with no diseased areas imaged (N=19), the relationship between presence of epithelial gaps and disease relapse was found to significantly depend on the number of areas imaged (p=0.01). Presence of epithelial gaps on pCLE was predictive of disease relapse when ≥ 3 areas were imaged (logrank p=0.02; C-statistic=0.94), but not when <3 areas were imaged (logrank p=0.32, C-statistic=0.60). Conclusion: In pediatric IBD patients, pCLE imaging of the terminal ileum was predictive of moderate to severe disease relapse, when at least 3 endoscopically normal areas were sampled.

*p<0.001 IFX Naive vs prior IFX (Poisson regression) Sa1153 Impact of Concomitant Immunosuppressant Use on Adalimumab Efficacy in Children With Moderately to Severely Active Crohn's Disease: Results From IMAgINE 1 Jeffrey S. Hyams, Frank Ruemmele, Richard B. Colletti, Jaroslaw Kierkus, Joel R. Rosh, Samantha Eichner, Andreas Lazar, Yao Li, Roopal Thakkar Background The impact of non-biologic immunosuppressants (IMMs) concomitantly administered with adalimumab (ADA) was evaluated in pediatric patients (pts) with moderately to severely active Crohn's disease (CD) in the randomized clinical trial IMAgINE 1 (NCT00409682). Methods In IMAgINE 1,1 pts aged 6-17 years with baseline Pediatric Crohn's Disease Activity Index (PCDAI) scores >30 and CD resistant or intolerant to conventional therapy, including prior infliximab, received open-label induction of ADA at weeks (wks) 0/2 according to body weight (≥40 kg, 160/80 mg; <40 kg, 80/40 mg). At wk 4, pts were randomized to double-blind higher-dose (HD) ADA (≥40 kg, 40 mg every other wk [eow]; <40 kg, 20 mg eow) or lower-dose (LD) ADA (≥40 kg, 20 mg eow; <40 kg, 10 mg eow). In pts meeting clinical response criteria, IMMs could be discontinued at or after wk 26. The proportion of pts receiving concomitant IMMs achieving clinical remission (PCDAI ≤10) at wk 26, and the proportion who discontinued IMMs and were in clinical remission or achieved clinical response (decrease in PCDAI of ≥15 from baseline) at wk 52 were evaluated. Non-responder imputation (NRI) was used for wk 26 outcomes when data were missing or pts had escalated dosing. In addition, modified NRI (mNRI) was used for wk 26 and 52 analyses, which considered pts as responders or non-responders after blinded dose escalation. Adverse events (AEs) in subpopulations by concomitant IMM were assessed. Results At baseline, 57 pts (60%) in the LD ADA group and 60 (64.5%) in the HD ADA group reported IMM use. At wk 26, clinical remission was achieved by 42/117 (35.9%) and 21/71 (29.6%) of ADA-treated pts with or without baseline IMMs, respectively (Table). Of the pts who achieved clinical remission at wk 26 (mNRI) and discontinued IMMs, 5/21 (23.8%) in the LD group and 6/27 (22.2%) in the HD group maintained clinical remission at wk 52. Of the pts who achieved clinical response at wk 26 (mNRI), 9/36 (25.0%) and 13/44 (29.5%), respectively, maintained clinical response at wk 52. The proportion of pts experiencing serious infectious AEs was similar in pts with (5.8%) or without (7.0%) concomitant IMMs. Of pts who developed anti-ADA antibodies (HD, n=4; LD, n=2), 1 in each dose group was on IMMs. Conclusion In children with moderate to severe CD treated with ADA, the rates of clinical remission with and without concomitant IMM use were not different. Concomitant IMMs did not affect the incidence of serious infections. 1. Hyams JS, et al. Gastroenterology. 2012;143:365-374. Proportion of Patients by IMM Use at Baseline Achieving Clinical Remission (PCDAI ≤10) at Week 26

Sa1155 Growth Pattern and Growth Failure in Paediatric Crohn's Disease Are Related to Inflammatory Status but Not to Duration of Steroid Therapy Hélène Béhal, Delphine Ley, Corinne Gower-Rousseau, Alain Duhamel, Mathurin Fumery, Francis Vasseur, Laurent Michaud, Isabelle Rousseau, Guillaume Savoye, Dominique Turck Growth failure is the main complication of paediatric-onset Crohn's disease (CD). The respective role of disease activity and steroid therapy in growth faltering is still a matter of debate. The aim of the present study was to investigate whether the growth pattern of children with CD was correlated with the evolution of inflammatory status during the disease course, whatever the cumulative duration of steroid therapy. Methods: 107 patients (63 boys and 44 girls) with a diagnosis of CD made at less than 17 years of age, followed in the same unit during ≥2 years and for whom ≥2 height measures were available during follow-up, were identified between 1998 and 2010. Height, C-reactive protein (CRP), orosomucoid and information on steroid therapy (including date of prescription and daily dose) were collected at each visit. Growth velocity was compared to the evolution of inflammatory status during follow-up in a longitudinal multivariate analysis using a mixed model. Results: Median age at CD diagnosis was 11.7 years (Q1-Q3: 9.8-13.5). Growth failure (Height/Age Z-score <-2) was present in seven patients (8%) at diagnosis and in five (5%) at maximal follow-up (median: 4.9 years; Q1-Q3: 3.8-6.4). Among the 75 patients who had achieved their growth at maximal follow up, mean Height/Age Z-score was 0.1 ± 1.2. Twenty patients (29%) reached their final height that was at least 4 cm below their target height. A total of 2112 height measures were available. Growth velocity was not influenced by the cumulative duration of steroid therapy (median: 7.1 months; Q1-Q3: 4.9-12.5), but was negatively correlated with the evolution of CRP (coefficient of the equation of regression (e) = -0.16; p < 0.0001) and orosomucoid (e = -0.60; p< 0.0001) during follow-up. Conclusion: CD children with uncontrolled inflammatory status have a lower growth velocity and a higher risk for growth failure, regardless of cumulative duration of steroid therapy. The inflammatory status should be kept normal as much as possible in paediatric-onset CD patients in order to optimize their growth pattern. Sa1156 Rising Incidence and Increasing Severity of Very Early Onset IBD in Ireland Rebecca Wylde, Aoife Carey, Billy Bourke, Annemarie Broderick, Shona Quinn, Mary Hamzawi, Karen Gleeson, Seamus Hussey

ADA=adalimumab; eow=every other week; IMM=immunosuppressant; PCDAI=Pediatric Crohn's Disease Activity Index.

AGA Abstracts

The literature describing the epidemiology and outcomes of very early onset IBD (VEOIBD) is limited. This study examined the epidemiology, phenotype and clinical outcomes of a national cohort of Irish children with VEO-IBD from 2000 to 2012. A retrospective review of all cases of VEO-IBD (those diagnosed <10 years of age) attending the Irish National Centre for Paediatric Gastroenterology from January 2000 to December 2012 was undertaken. Patient demographics, diagnostic work-up, initial and subsequent treatment, and long term clinical and surgical outcomes at 1, 2, 5 and/or maximum clinical follow up were recorded. Cases were phenotyped according to the Paris classification and clinical activity was determined using PGA, PCDAI and PUCAI scores. Poisson regression analysis was used to calculate incidence trends. One hundred and fifty eight children (50% male) with VEO-IBD were identified; 78 (49%) had Crohn Disease (CD), 63 (40%) had Ulcerative Colitis (UC) and

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