Sa1199 Fatigue in IBD Patients Decreases With Psychotherapy: Results of a Randomized Controlled Trial

AGA Abstracts Sa1198 Vitamin D Supplementation Improves Muscle Strength, Fatigue and Quality of Life in Patients With Crohn's Disease in Remission: Results of a Randomized Double-Blind Placebo-Controlled Study Tara C. Raftery, Martin Healy, Gerry Cox, Deirdre McNamara, Maria O'Sullivan CONTEXT: Reduced muscle strength, fatigue and poor quality of life (QoL) are frequently reported in Crohn's disease (CD) even in remission. There is growing evidence that vitamin D (vitD) may alter skeletal muscle function and strength. Our aim was to investigate the effects of vitD supplementation on muscle function and, correspondingly, on fatigue and QoL in patients with stable CD. METHODS: In a double-blind placebo-controlled study, 27 subjects with CD in remission were randomized to 2000 IU vitD3/d or placebo for 3mo. The primary outcome measures were changes in hand-grip strength (HGS) (Jamar Digital Hand Dynamometer), fatigue (Multi-fatigue inventory, MFI) and QoL (Inflammatory Bowel Disease questionnaire, IBDQ) at 3mo. At 0 and 3mo, disease activity (CD activity index, CDAI)), FBC, CRP (mg/l) and serum 25-hydroxy vitD (25OHD) (nmol/l) were also measured. RESULTS: At enrolment mean (sem) CRP [2.39 (0.53)] and CDAI [92.35 (13.23)] were consistent with disease remission and Hb and haemocrit were within normal ranges. At 3mo, serum 25OHD increased significantly in the treated group [69.2 (7.0) to 91.6 (25.3) nmol/l, p=0.002] and decreased in the controls [51.8 (20.7) to 40.4 (14.9) nmol/l, p=0.021]. Baseline HGS was matched in the VitD-treated and placebo groups, with no difference in either dominant [treated: 80.2 (7.8); placebo: 66.7 (7.6), p =0.20] or non-dominant HGS [treated: 78.6 (9.9), placebo: 64.8 (7.2), p = 0.26) between the groups. Post-intervention, both dominant (fig 1) and non-dominant (fig 2) HGS were significantly higher in the VitDtreated group. At 3mo, patients who achieved 25OHD levels .=75nmol/l had significantly higher QoL [mean (sem)] compared to patients below this cut-off [IBDQ score 187.3 (2.3) v. 163.2 (2.1), p=,0.0001]. Furthermore, bowel and social domains of the IBDQ showed significant improvement in those achieving .=75nmol/l 25OHD compared to those who did not [Bowel 60.5 (1.9) v. 51.5 (2.7), p=0.015; Social 59.4 (6.3) v. 44.5 (4), p=0.05]. In line with this, significantly less fatigue [mean (sem)] was experienced in those with 25OHD levels .=75nmol/l v. those below this cut-off, as assessed by both question 2 of the IBDQ [5.0 (0.4) v. 3.6 (0.4), p=0.032] and the MFI [20.4 (1.3) v 26.5 (3.1), p=0.08]. This finding was consistent in each of the MFI sub-domains, namely physical and general fatigue, activities of daily living and mental fatigue. CONCLUSION: Oral daily supplementation with 2000IU vitd3/d for 3mo significantly increased dominant and non-dominant HGS compared to placebo. Achieving serum 25OHD levels of 75nmol/l or greater was associated with increased QoL and reduced fatigue scores. These findings, to our knowledge, are the first to suggest potential benefits of vitD on muscle strength with corresponding benefits for fatigue and QoL in CD, and merit investigation in larger controlled studies.

Sa1199 Fatigue in IBD Patients Decreases With Psychotherapy: Results of a Randomized Controlled Trial Lauran Vogelaar, Adriaan van 't Spijker, Reinier Timman, Antonie J.P. van Tilburg, DirkJan Bac, Ernst J. Kuipers, Jan Busschbach, Christien J. van der Woude Background Inflammatory bowel disease(IBD) is associated with severe fatigue and subsequently decreased Quality of Life(QoL). Little is known about the fatigue management in IBD patients.Earlier we showed the feasibility of psychotherapy in IBD patients.With this randomized controlled trial we aimed to assess the effectiveness of Solution Solution Focused Therapy(SFT) on the severity of fatigue. Methods Patients with quiescent IBD measured by activity disease indexes and calprotectin and a high fatigue score according to the Checklist Individual Strength (above 35 on CIS-fatigue subscale) were randomized to SFT or to a control group.They completed questionnaires including the Hospital Anxiety and Depression Scale(HADS),the Crohn's Disease Index(CDAI) or the Clinical Activity Index(CAI),the Inflammatory Bowel Disease Questionnaire(IBDQ),the Short Form-36(SF-36),the EuroQol(EQ5D),the Pittsburgh Sleep Quality Index(PSQI)and a questionnaire focusing on current medication use and side-effects. The Montreal classification and sociodemographics were obtained from medical records.Follow-up was 6 months. Results Ninety-eight patients were included (58.8% CD patients and 41.2% UC patients)of these 63% were female,mean age was 40.1 years.At baseline the treatment group showed a mean CIS-fatigue of 46.6 compared with a mean of 46.3 in the control group (p=0.759). At baseline no differences were observed

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AGA Abstracts

AGA Abstracts

between the treatment group and the control group according to the baseline characteristics,the QoL questionnaires, the HADS and the PSQI, medication, side-effects, disease phenotype, surgery and laboratory parameters. At 3 months the treatment group showed significant improvement on the CIS-fatigue (treatment:37.8, control:42.6;p=, 0.001), CIS-total (treatment:83.5, control:93.4;p=0.001),IBDQ (treatment:173.3,control: 166.7;p=0.020)and SF36 physical(treatment:43.8, control:41.2;p=0.049) compared with the control group. The effect size was medium for CIS-fatigue and for CIS-total at 3 months (p= , 0.001). For IBDQ and SF-36 physical the effect size was smal (p=0.02 and p=0.049, respectively).At 6 months this positive effects sustained for the CIS-fatigue and CIS-total. Gender nor IBD subtype had a significant influence on the results. Conclusions SFT decreased significant fatigue and increased QoL of IBD patients. This effect did not sustained during followup.Therefore, psychological treatment is effective in reducing fatigue in IBD patients, but repeating courses are warranted for long-term fatigue control.

Table 1

*- adalimumab conc for HD were higher (p ,0.001) than LD Sa1202 Relationships Between Clinical Remission, C-Reactive Protein Normalization and Mucosal Healing in Crohn's Disease: Analyses From the SONIC trial Laurent Peyrin-Biroulet, Walter Reinisch, Jean-Frederic Colombel, Gerassimos J. Mantzaris, Asher Kornbluth, Robert Diamond, Paul J. Rutgeerts, Kezhen L. Tang, Freddy J. Cornillie, William Sandborn

Sa1200 Identifying Crohn's Disease Cases for Clinical Trials: Data From the Novel Biomarkers in Inflammatory Bowel Disease (NBIBD) Project Cohort James D. Falvey, Teagan S. Hoskin, Berrie Meijer, Anna L. Ashcroft, Mark B. Hampton, Andrew S. Day, Richard B. Gearry

Background: The Crohn's Disease Activity Index (CDAI) has been criticized due to heavy weighting on subjective clinical symptoms such as abdominal pain, and decreased sense of well-being. The biomarker C-reactive protein (CRP) and endoscopic lesions are objective measures of inflammation. We investigated the relationships between clinical remission, CRP normalization and mucosal healing in Crohn's disease (CD) in the SONIC trial. Methods: The SONIC trial was a randomized, controlled trial comparing infliximab to azathioprine and to infliximab plus azathioprine for the treatment of 508 patients with CD who were Naïve to both immunomodulators and biologic therapy. CD activity, as measured by the CDAI, CRP and ileocolonoscopy, was evaluated at baseline and at week 26. Mucosal healing was defined as the absence of mucosal ulceration at the week 26 ileocolonoscopy in a patient who had evidence of ulceration present at the baseline ileocolonoscopy. Results: A total of 188 patients who had evidence of mucosal ulceration at baseline, evaluable ileocolonoscopy, CDAI scores and CRP values at baseline and week 26 were included in this analysis. 140/ 188 patients (74.5%) had baseline elevated CRP (CRP ≥ 0.5 mg/dL). Seventy-two of 136 patients (52.9%) who were in clinical remission (CDAI , 150) at week 26 achieved mucosal healing, while 54 (39.7%) achieved both CRP normalization (CRP , 0.5 mg/dL) and mucosal healing. The sensitivity and specificity of CDAI remission and CDAI moderate-to-severe disease activity to predict mucosal healing and CRP normalization in CD are provided in Table 1. The PPV and NPV of CDAI to detect mucosal healing using 150 as a cutoff for CDAI were 65.4% and 52.9%, and 80.8% and 39.7% to detect mucosal healing and/or CRP normalization, respectively. Among the 27 patients (14.4%) who had persistent moderateto-severe disease (CDAI ≥ 220) at week 26, 8 (29.6%) achieved mucosal healing and 6 (22.2%) achieved both CRP normalization and mucosal healing. The PPV and NPV of CDAI to detect mucosal healing using 220 as a cutoff for CDAI were 70.4% and 50.9%, respectively and 77.8% and 36% to detect mucosal healing and/or biomarker remission, respectively. Conclusions: Half of CD patients in clinical remission have endoscopic and/or CRP evidence of residual active CD, whereas other patients with endoscopic and CRP normalization have persistent clinical symptoms. These findings demonstrate that CD clinical symptoms as scored by CDAI are not a reliable measure of the underlying inflammation. Objective outcome measures of CD activity beyond clinical symptoms need to be further evaluated. Table 1: Sensitivity and specificity of CDAI remission and CDAI moderate-to-severe disease activity to predict mucosal healing and CRP normalization in CD

Introduction: Clinical trials in Crohn's disease are hampered by high placebo response rates that impair statistical power to detect treatment effects. This results from the inclusion of individuals with little or no mucosal inflammatory activity by inclusion criteria that are based on symptom severity alone. Post-hoc analysis of data from major international trials indicates that individuals with biochemical evidence of inflammatory disease have higher rates of treatment response. Standard inclusion criteria for clinical trials (CDAI ≥220 ≡ Harvey Bradshaw Index (HBI) ≥8) are poorly validated with respect to endoscopic mucosal activity, and prospectively derived combined clinical/biochemical thresholds have not been identified. Aims: To determine appropriate combined clinical (HBI)/biochemical inclusion criteria for use in clinical trials. Methods: Patients attending for colonoscopy with known or suspected IBD were recruited. Cases provided disease activity data (HBI) and blood for CRP measurement. Endoscopic activity was recorded using the simple endoscopic score of Crohn's disease (SES-CD. Inactive, 0-2; mild, 3-6; moderate, 7-15; severe, ≥16). ROC analysis was used to determine the predictive value and optimal predictive thresholds for HBI and CRP. Significance thresholds were adjusted by Bonferroni's method. Optimal predictive thresholds were those with highest accuracy and/or Youden's index. Results: 108 CD cases were included. Median (IQR) SES-CD, 4 (2-12). Spearman correlation coefficients for comparison with SES-CD were: HBI r=0.24 (p=0.007); CRP, r=0.44 (p ,0.0001). HBI had significant diagnostic utility for severe, but not mild or moderate disease (AUC 0.78 (p= 0.0002), AUC 0.58 (p=0.2) and AUC 0.62 (p=0.04(ns)) respectively). The optimal threshold for severe disease was HBI ≥8 (≡CDAI ≥220). The sensitivity, specificity, PPV and NPV of HBI≥8 for severe endoscopic CD were 71%, 80%, 40% and 94% respectively. 20% of those with HBI ≥8 had inactive endoscopic disease. ROC curve analysis for CRP was performed for cases with HBI≥8 (n=29). CRP only had significant diagnostic utility for detecting at least severe endoscopic disease (AUC 0.83, p=0.003). The optimal threshold for identifying severe CD when HBI≥8 was 10 mg CRP/L. The sensitivity, specificity, PPV and NPV of CRP ≥10mg/L for severe disease when HBI ≥8 were 82%, 72%, 64% and 87% respectively. For those fulfilling these criteria, 79% had at least moderate disease, 64% at least severe disease and none had inactive endoscopic disease. For the whole dataset, the sensitivity, specificity, PPV and NPV of these criteria to detect any endoscopic activity were 18%, 100%, 100% and 32% respectively Conclusion: Case selection for clinical trials of CD by the criteria HBI≥8 (≡CDAI ≥220) and CRP≥10mg/L is optimal for the selection of CD cases with active mucosal disease. Sa1201 Pharmacokinetics of Adalimumab in Pediatric Patients With Moderate to Severe Crohn's Disease Doerthe Eckert, Sven Mensing, Shringi Sharma, Roopal Thakkar, Anne Robinson, Jeffrey S. Hyams, Joel R. Rosh, Frank Ruemmele, Walid M. Awni

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Background: To characterize the pharmacokinetics (PK) of adalimumab in pediatric patients (pts) with moderate to severe Crohn's disease (CD). Methods: Trough serum adalimumab and anti-drug antibody (AAA) concentrations (conc) were measured in a 52-week (wk) study (N=189), which had a 4-wk open-label induction phase (dose was determined by pt weight) followed by a 48-wk double-blind maintenance phase (high and low-dose arms). Pts with inadequate response could increase from eow to ew dosing. A non-linear mixed effects modeling (NONMEM®) approach was used. Results: At wk 4, the mean±SD adalimumab conc (μg/mL) for pts ≥ 40 kg, 15.7 ± 6.55 (160/80 mg), was higher (p ,0.001) than for pts , 40 kg, 10.6 ± 6.06 (80/40 mg). For the maintenance phase, the mean±SD adalimumab conc (μg/mL) are shown in Table 1. Pts receiving ew dosing had higher adalimumab conc at wk 52 (HD: 15.3 ± 11.4, p=0.065; LD: 6.65 ± 3.49, p=0.002) compared to those on eow. Anti-TNF Naïve pts had slightly higher adalimumab conc than those with prior anti-TNF exposure. Among pts with prior anti-TNF exposure, those with immunogenicity to prior anti-TNF had slightly lower adalimumab levels than those without. Six pts (6/ 182, 3.3%) were AAA positive during the study; and adalimumab conc were lower in those pts. Pts on concomitant immunosuppressants (azathioprine, 6-mercaptopurine & methotrexate; IMM) had slightly lower (~18%) adalimumab clearance (12.4±5.74 mL/h) compared to pts without IMM (15.2±7.88 mL/h). Only body weight was identified as a statistically significant covariate; but, it explained only 2.6% of total PK variability. A combination of multiple covariates of interest (body weight, albumin, age, sex, CRP, and concomitant IMM) was able to explain , 13% of total PK variability. Conclusion: Adalimumab trough conc were maintained in pts receiving eow regimen for 52 wks. Dose escalation was associated with an increase in adalimumab conc compared to eow dosing. Pts with prior anti-TNF exposure (especially those with immunogenicity to prior anti-TNF) tended to have lower adalimumab conc compared to anti-TNF Naïve pts. Body weight was the only statistically significant baseline covariate affecting adalimumab clearance, but it accounted for ,3%of PK variability.

AGA Abstracts

Pharmacokinetics and Exposure-Response Relationship of Golimumab in Patients With Moderately to Severely Active Ulcerative Colitis: Results From Phase2/3 Induction and Maintenance Studies Omoniyi J. Adedokun, Zhenhua Xu, Colleen W. Marano, Richard Strauss, Hongyan Zhang, Jewel Johanns, Joyce A. Ford, Honghui Zhou, Hugh M. Davis, Jean-Frederic Colombel, Walter Reinisch, Brian G. Feagan, Paul J. Rutgeerts, William Sandborn Background & Aims: Pharmacokinetics (PK) and exposure-response (ER) relationship data of golimumab (GLM) from the PURSUIT-SC induction and maintenance studies in UC are evaluated. Methods: PURSUIT-SC induction was an integrated Phase 2 dose-finding/ Phase 3 confirmatory study. UC patients with Mayo scores of 6-12 inclusive, including endoscopic subscore .2, were randomized to placebo (PBO)/PBO (n=331); GLM 100 mg/50 mg (before Ph3 dose selection only, n=72); GLM 200 mg/100 mg (n=331); GLM 400 mg/200 mg (n= 331) at wks0&2. The Phase 3 maintenance study enrolled 1228 patients from PURSUITIV & PURSUIT-SC induction studies. The primary analysis population consisted of patients (n=464) who responded to GLM induction & were randomized to receive PBO, GLM 50 mg, or GLM 100 mg at baseline (wk0) & q4wks through wk52. Serum GLM concentrations (SGC) were measured from blood samples collected at scheduled visits through wk6 during induction and through wk54 during maintenance. Results: Median SGC peaked at wk2 of induction in all dose groups with concentrations of 2.34 μg/mL, 6.27 μg/mL and 11.95 μg/ mL for the 100 mg/50 mg, 200 mg /100 mg, 400 mg/200 mg grps, respectively. At wk6, median SGC were 0.78 μg/mL, 1.78 μg/mL, and 4.01 μg/mL respectively. SGC were approximately dose-proportional during induction and maintenance. SGC were sustained reaching steady-state approximately 8wks after start of GLM maintenance (or a total of 14wks after initiation of GLM therapy) regardless of induction dose. Median preadministration (trough) SGC from Week 8 through Week 44 of the maintenance study, ranged from 0.69 to 0.83

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