Average Stool Frequency Research Articles

Additional criteria on scintigraphic testing for diagnosis of rapid colonic transit in patients with chronic diarrhea.

Colonic transit (CT) measured by validated scintigraphy using 111In-labeled activated charcoal particles is summarized using geometric center (GC) of isotopic distribution in four colonic regions and stool at 24 and 48 h. Diagnosis of rapid CT is currently based on GC24 ≥4.4 in females and >4.7 in males, which lack sensitivity. Our aim was to evaluate, in patients with chronic diarrhea with normal CT by GC24 and GC48, the diagnostic utility of CT change (∆GC) relative to sex-matched normal values. We evaluated two adult patient cohorts: 701 clinical patients (1994-2023) with chronic diarrhea and 76 research participants with irritable bowel syndrome with diarrhea (N = 63) or bile acid diarrhea (BAD, N = 13). Results of ∆GC were compared to 220 healthy controls' 95th percentiles (%ile) (≥2.0 females and ≥2.2 males). In the research cohort, we also analyzed (Spearman correlation) colonic ∆GC with ascending colon emptying T1/2 (AC T1/2), average stool frequency and consistency based on a daily diary, total fecal bile acid (BA) concentration, and % primary BA in a single stool sample. Among 701 clinical patients with normal GC24, 160 (22.3%) had rapid CT based on ∆GC 95th %ile in health. Among 76 research participants, an additional 20.6% IBS-D and 23% BAD had rapid CT ∆GC. Younger age and absence of diabetes mellitus were predictive of rapid ∆GC. ∆GC significantly correlated with AC T1/2 and with fecal BA. ∆GC identified an additional 21%-23% patients with rapid colonic transit among patients with diarrhea and normal GC24.

The post-COVID-19 intestinal damages: clinical, endoscopic and morphological features. The results of a single-center prospective observational cohort study

Background: Clinical signs of gastrointestinal disorders can manifest both from the first days of COVID-19 and after recovery, and may last up to 6 months or more. Most studies examined the gastrointestinal changes in acute coronavirus infection, whereas intestinal abnormalities in the early and late post-COVID period and their causes have not been sufficiently studied.
 Aim: To determine the frequency and types of clinical, endoscopic and morphological abnormalities in patients with post-COVID-19 intestinal lesions.
 Materials and methods: This was a prospective, observational, open-label, cohort, non-controlled study in 72 patients with intestinal symptoms after the coronavirus infection (female 48, mean age 54.6 (95% confidence interval 51.08–58.12) years), who were admitted to the Department of Gastroenterology of general hospital during the first and second waves of COVID-19 from June 2020 to September 2021. The assessment included routine anamnestic, clinical, laboratory, endoscopic, and morphological methods. When indicated, visualization methods (ultrasound, computed tomography, magnetic resonance imaging) were performed. The treatment was symptom-oriented and aimed at inflammation, anemia and protein and electrolyte abnormalities. Outcomes were assessed by the time of discharge from the hospital and thereafter by telephone interviewing of the patients for 8 weeks.
 Results: In all patients, the main symptom was diarrhea, which started right just after SARS-CoV-2 infection with negative PCR test or 2–4 weeks later. The average stool frequency was 6.8 (5.61–7.99) times daily. In 19/72 patients (26.4%), there were blood and mucus in stools. 2.8% of the patients developed massive intestinal bleeding. Fever was present in 40.3% of the patients, decreased hemoglobin levels in 44.4%, and hypoalbuminemia in 16.7%. Signs of systemic inflammation (increased erythrocyte sedimentation rate, C-reactive protein, fibrinogen, thrombocytosis, leukocytosis) were found with various frequencies in a half of the patients. Clostridioides difficile A and B toxins were identified in 38.9% of the cases and increased fecal calprotectin in 22.2%.
 Ileocolonoscopy was performed in 67 patients. The colonic mucosa in 21 (31.3%) patients either was not different from the normal, or showed minimal inflammatory changes such as absence of vascular pattern, hyperemia, mild friability even in patients with severe diarrhea, fever and laboratory abnormalities. Pseudomembranous colitis was diagnosed in 12 (17.9%) patients, and focal hemorrhagic colitis in 11 (16.4%) patients. In 2 (3%) cases, moderate to severe ulcerative colitis was newly diagnosed after the SARS-CoV-2 infection. Single or multiple erosions and ulcers of various sizes against the unchanged surrounding mucosa were found in 19 (28.4%) patients. In 2 (3%) cases with profuse intestinal bleeding, the endoscopy showed diffuse spontaneous bleedings from colonic mucosa, with no local source of bleeding found.
 Biopsy samples from colonic mucosa were taken from 47 patients. Morphological abnormalities of only moderate or dense lymphoplasmocytic infiltration were detected in 29 (67.7%) patients, erosions in 8 (17%). In 2 (4.3%) cases, highly dense lymphoid infiltration with neutrophils, eosinophils and crypt abscesses was found, as typical for ulcerative colitis. In 2 (4.3%) patients, the lymphoid infiltration was associated with small venular and arteriolar clots, and in 5 (10.6%) patients there were no significant morphological abnormalities, except mild lymphoid infiltration.
 During the hospitalization period, 56.9% of the patients showed a decrease in stool frequency, improvement of clinical and laboratory signs of systemic inflammation and metabolic abnormalities, and partial restoration of their body weight. One patient with ulcerative colitis received adalimumab and achieved stable clinical and endoscopic remission. Complete recovery was noted in 27.8% of the cases within 4–8 weeks, among them in 1 patient who had had profuse intestinal bleedings. In 3 cases (4.2%), an emergency colectomy was performed due to severe pseudomembranous colitis. Two (2.8%) deaths were registered: one patient with newly diagnosed post-COVID severe ulcerative colitis died of pneumonia, and another patient died of severe multiorgan failure. In 6 (8.3%) cases, a moderate long-term (above 8 weeks) diarrhea with metabolic disorders, weight loss, but without systemic inflammation was noted.
 Conclusion: In patients with post-COVID intestinal lesions, the clinical symptoms are almost the identical and manifest with diarrhea of varying severity, systemic inflammation and metabolic disorders, whereas the endoscopic and morphological lesions are quite diverse. The severity of clinical symptoms often does not correspond to poorly expressed endoscopic and morphological signs. The variability and inconsistency of the clinical, endoscopic and morphological changes have not yet been systematized and do not allow for a clearly formulated diagnosis (except cases of pseudomembranous and ulcerative colitis). This makes it impossible to provide pathophysiologically-based treatments.

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.

P661 Clinical response over 24 weeks for initial and delayed responders to induction therapy with risankizumab in Crohn’s disease: data from the ADVANCE and MOTIVATE studies

Abstract Background The efficacy and safety of risankizumab (RZB) in patients with Crohn’s disease (CD) has been demonstrated.1,2 We reported that an additional 12 weeks (ie, induction period 2) of RZB therapy could induce clinical response in patients with CD who did not achieve clinical response after an initial 12-week induction period.3 In this post hoc analysis, we report the proportion of patients who achieved clinical response over 24 weeks (initial and delayed responders to RZB induction therapy). Methods Data were pooled from the ADVANCE and MOTIVATE phase 3 RZB studies. Patients who had not achieved stool frequency (SF)/abdominal pain score (APS) clinical response (≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily APS and both not worse than baseline) after an initial 12-week induction with intravenous (IV) RZB (600 mg or 1200 mg) at weeks 0, 4, and 8 were rerandomized 1:1:1 in induction period 2 to receive IV RZB 1200 mg (at weeks 12, 16, and 20) or subcutaneous (SC) RZB (180 mg or 360 mg at weeks 12 and 20) in a double-dummy–blinded fashion. In this post hoc analysis, efficacy was analysed in patients treated with either 600 mg RZB IV or placebo (PBO) for 12 weeks in the PBO-controlled induction period and patients who did not achieve clinical response with 600 mg RZB IV for 12 weeks and were rerandomized to 360 mg RZB SC every 8 weeks during induction period 2 (currently marketed RZB doses). SF/APS clinical response was assessed at week 12 for initial responders and at week 24 for delayed responders in induction period 2. Non-responder imputation with no special data handling for data missing due to COVID-19 was used. No multiplicity adjustment was performed. Results Of the 889 patients randomised to 600 mg IV RZB or PBO in the induction studies, 70.0% (369/527) in the RZB group compared with 45.6% (165/362) in the PBO group achieved SF/APS clinical response at week 12. Of the 47 patients who did not achieve initial clinical response to 600 mg IV RZB and received 360 mg SC in induction period 2, 32 (68.1%) achieved delayed SF/APS clinical response at week 24. The proportion of patients achieving SF/APS clinical response over 24 weeks (either initial or delayed responders) was 89.1% (401/450). The safety profile of RZB in patients with CD has been reported.1,2 Conclusion In patients with moderate-to-severe CD, RZB treatment leads to approximately 9 of 10 patients achieving either initial (600 mg IV) or delayed (600 mg IV followed by 360 mg SC) clinical response over 24 weeks.

S736 Efficacy and Safety of Upadacitinib Induction Therapy in Patients With Moderately to Severely Active Crohn’s Disease: Results From a Randomized Phase 3 U-EXCEL Study

Introduction: Eligible patients(N=526) with moderate to severe active Crohn’s Disease(CD), defined as average daily stool frequency(SF)≥4 and/or abdominal pain score(APS)≥2, and a Simple Endoscopic Score for CD(SES-CD) (excluding the narrowing component subscore) ≥6(≥4 for subjects with isolated ileal disease). Methods: Patients(pts) were randomized 2:1 to UPA45 or PBO for 12 weeks(wks). Pts on baseline corticosteroids(CS) initiated a protocolized tapering at wk4. The co-primary endpoints, clinical remission(per CDAI for US [CDAI< 150] or per SF/APS for EU [average daily SF ≤2.8 and APS≤1.0 and neither greater than baseline [BL]) and endoscopic response(decrease in SES-CD >50% from BL or ≥2-point reduction from BL for pts with a BL SES-CD=4), were evaluated at wk 12. Safety, primary and key secondary clinical, and endoscopic outcomes were evaluated through wk 12. Results: BL demographics and characteristics were similar between groups; 45.4% of pts had a history of prior biologic use or failure. At wk 12, significantly more pts receiving UPA45 vs PBO achieved the co-primary endpoints: clinical remission(per CDAI, UPA45 49.5% vs PBO 29.1%; per SF/APS, UPA45 50.7% vs PBO 22.2%) and endoscopic response (UPA45 45.5% vs PBO 13.1%) (P< .0001 for all endpoints; Table). UPA45 was superior to PBO for most of the ranked secondary endpoints including clinical remission per CDAI and SF/APS at wk 4, CS-free clinical remission per CDAI and SF/APS at wk 12, clinical response(CR-100; 100-point decrease in CDAI from BL at wk 2 and wk 12, and endoscopic remission at wk 12(P< .0001 or P< .01, Table). Severe AEs occurred at 8.9% and 8.5% within UPA45 and PBO groups, respectively. The most common AEs(≥5% of pts) were acne and anemia among pts treated with UPA, and CD exacerbation among pts receiving PBO. Serious infections were 1.1% and 1.7% for UPA45 and PBO groups, respectively. Herpes zoster(2.9%) was reported in the UPA45 group only, and an adjudicated cardiovascular event(0.6%) was reported only in the PBO group. No treatment-emergent deaths, malignancies, other opportunistic infections, adjudicated gastrointestinal perforations or adjudicated thrombotic events were reported in either group. Conclusion: UPA45 induction therapy was superior to PBO in achieving early response, including clinical remission, endoscopic response, and CS-free clinical remission during the U-EXCEL study. UPA45 was well tolerated, with no new safety risks and a safety profile comparable to previous UPA studies. Table 1. - Co-primary and Key Secondary Endpoints Endpoint PBO (N=176)% [95% CI] g UPA 45 mg QD (N=350)% [95% CI] g Difference vs. PBO% [95% CI] h Co-Primary Endpoints Clinical remission, wk 12 Per CDAI a Per SF/APS b 29.1 [22.4, 35.8]22.2 [16.0, 28.3] 49.5 [44.2, 54.8]50.7 [45.5, 56.0] 20.8 [12.7, 28.8]**28.7 [20.9, 36.4]** Endoscopic response c , wk 12 13.1 [8.1, 18.0] 45.5 [40.3, 50.8] 33.0 [26.2, 39.9]** Key Secondary Endpoints Clinical Remission, wk 4 Per CDAI a Per SF/APS b 26.7 [20.2, 33.3]14.8 [9.5, 20.0] 37.1 [32.1, 42.2]35.7 [30.7, 40.7] 10.8 [2.9, 18.6]*21.2 [14.3, 28.2]** Corticosteroid-free clinical remission, wk 12 per CDAI d per SF/APS d (N=64)15.7 [6.8, 24.7]12.5 [4.4, 20.6] (N=126)42.9 [34.2, 51.5]44.4 [35.8, 53.1] 27.7 [15.7, 39.8]**32.6 [21.5, 43.7]** Clinical Response CR-100 e Week 2 Week 12 20.4 [14.4, 26.5]37.3 [30.1, 44.5] 32.2 [27.3, 37.1]56.6 [51.4, 61.8] 11.7 [4.2, 19.2]*19.8 [11.3, 28.4]** Endoscopic remission f , wk 12 7.4 [3.5, 11.3] 28.9 [24.2, 33.7] 21.8 [15.8, 27.8]** Patient randomization was stratified by baseline corticosteroid use, endoscopic disease severity, and the number of previously failed biologics. All patients within this dataset were included here within the ITT population.aClinical remission per CDAI = per US, CDAI < 150.bClinical remission per SF/APS = per EU, average daily SF ≤ 2.8 and average daily APS ≤ 1.0 and both not greater than baselinecEndoscopic response = decrease in SES-CD > 50% from baseline (or for subjects with a baseline SES-CD of 4, at least a 2-point reduction from baseline), as scored by a central reviewer.dCorticosteroid-free clinical remission = discontinuation of corticosteroid use and achievement of clinical remission per CDAI or SF/APS at wk 12 among patients on corticosteroids at baseline.eClinical response-100 = decrease of ≥ 100 points in CDAI from baseline.fEndoscopic remission = SES-CD ≤ 4, at least a 2-point reduction versus baseline and no subscore >1 in any individual variable, as scored by a central reviewer.gResults are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C).h95% CI for adjusted difference and p-value are calculated according to the Cochran-Mantel-Haenszel (CMH) test adjusted for randomization strata.**P ≤ .0001 or *P ≤ .01 vs PBO; Average daily abdominal pain score, APS; Coronavirus disease 2019, COVID-19; Confidence Interval, CI; Crohn’s Disease Activity Index, CDAI; Simple Endoscopic Score for CD, SES-CD, Placebo, PBO; Once daily, QD; average daily very soft/liquid stool frequency, SF; Upadacitinib, UPA.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials

Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. AbbVie.

Incorporating patient experience into drug development for ulcerative colitis: development of the Urgency Numeric Rating Scale, a patient-reported outcome measure to assess bowel urgency in adults

BackgroundBowel urgency, the sudden or immediate need to have a bowel movement, is a common, bothersome and disruptive symptom of ulcerative colitis (UC). UC treatment goals include control of urgency; however, it is not consistently assessed in UC clinical trials. The Urgency Numeric Rating Scale (NRS) is a new patient-reported measure to assess severity of bowel urgency in adults with UC developed in accordance with Food and Drug Administration guidelines.MethodsQualitative interviews were used to develop Urgency NRS. The scale asks patients to report the immediacy status of their UC symptom over the past 24 h on an 11-point horizontal numeric rating scale [0 (No urgency) to 10 (Worst possible urgency)]. Higher scores indicate worse urgency severity. A 2-week diary study assessed floor and ceiling effects, test–retest reliability (intraclass correlation coefficient (ICC) (2,1) between Week 1 and 2), and construct validity (Spearman correlation using Week 1 scores). Weekly scores were calculated as mean score over each 7-day period.ResultsQualitative interviews with 16 UC patients (mean age 37.9 ± 11.6 years; 50% female; 56% White) confirmed relevance, content, and comprehensiveness. The 2-week diary study included 41 UC patients (mean age 44.2 ± 14.6 years; 51% female; 56% White). No ceiling or floor effects were identified. Test–retest reliability was high (ICC = 0.877). Average Urgency NRS and patient global rating of severity scores were highly correlated, with a moderate correlation between average Urgency NRS and stool frequency, demonstrating construct validity.ConclusionsBowel urgency is a distinct symptom of UC. The Urgency NRS is a well-defined, content-valid, and reliable measurement of bowel urgency in adults with UC.

DOP85 Efficacy of risankizumab rescue therapy in patients with moderately to severely active Crohn’s Disease and inadequate response to risankizumab maintenance therapy

Abstract Background The efficacy and safety of 12 weeks of induction and 52 weeks of maintenance treatment with risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with moderately to severely active Crohn’s disease (CD) was previously demonstrated in 3 phase 3 trials (ADVANCE, MOTIVATE, and FORTIFY). We investigated outcomes in patients with inadequate response to subcutaneous (SC) RZB or SC placebo (PBO) treatment and required RZB rescue therapy during maintenance. Methods In FORTIFY, a phase 3, double-blind, re-randomised responder withdrawal, maintenance study (NCT03105102), patients that responded to 12 weeks of RZB IV induction received RZB 180 mg SC, RZB 360 mg SC, or PBO (ie, withdrawal) every 8 weeks for 52 weeks. Starting at week 16, patients with inadequate response, defined as average daily stool frequency [SF] ≥ 3.3 and/or average daily abdominal pain score [APS] ≥ 1.5 as well as high-sensitivity C-reactive protein ≥ 5 mg/L and/or faecal calprotectin ≥ 250 μg/g; or Simple Endoscopic Score for CD (SES-CD) ≥ 6 (≥ 4 for isolated ileal disease), excluding the narrowing component as scored by the site Investigator, were eligible to receive open-label rescue therapy (1 dose of intravenous [IV] RZB 1200 mg, followed by RZB 360 mg SC every 8 weeks). Up to 2 rescue therapy visits ≥ 16 weeks apart were permitted. Efficacy at week 52 was assessed in the intent-to-treat population using nonresponder imputation for missing data. Patients were also considered nonresponders when maximum equivalent steroid dose exceeded the dose used at baseline or if patients initiated any new steroids. Safety was assessed throughout the study. Results In the maintenance study, a greater proportion of patients in the withdrawal (PBO SC) arm (40.2% [66/164]) were administered RZB rescue therapy vs RZB 180 mg SC (24.2% [38/157]) and RZB 360 mg SC (21.3% [30/141]; Figure A); most patients (71.1%–81.8%) required 1 rescue visit, and 16.7%–26.3% required 2 visits. Median time to first RZB rescue therapy was 178 days for the withdrawal (PBO SC) group, 179 days for the RZB 180 mg SC group, and 154 days for the RZB 360 mg SC group. At week 52, 52.5%–75.0% of patients who received RZB rescue therapy achieved SF/APS clinical response (Figure B), and 20.0–36.4% of patients who received rescue therapy achieved clinical remission (per CDAI or SF/APS) and/or endoscopic response (Figures C-E). The safety profile of RZB in CD has previously been reported. Conclusion RZB rescue therapy (one dose of RZB 1200 mg IV followed by RZB 360 mg SC every 8 weeks) may be beneficial to patients with moderately to severely active CD experiencing inadequate response to or interruption in RZB maintenance treatment.

DOP83 Normalisation of biomarkers and improvement in clinical outcomes in patients with Crohn’s Disease treated with risankizumab in the phase 3 ADVANCE, MOTIVATE, and FORTIFY studies

Abstract Background The efficacy of risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with Crohn’s disease (CD) has been reported. Normalisation of high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) are intermediate treatment targets in CD. Here, we evaluated changes in these objective inflammatory biomarkers and clinical outcomes with RZB treatment. Methods In 2 phase 3, randomised, double-blind studies (ADVANCE, NCT03105128; MOTIVATE, NCT03104413), patients with moderately to severely active CD received 12-week intravenous (IV) RZB induction therapy or placebo (PBO). Patients with clinical response to RZB IV induction were rerandomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, RZB withdrawal). Induction analyses included patients who received either 600 mg RZB IV or PBO for 12 weeks. Maintenance analyses included patients who received 360 mg RZB SC every 8 weeks or withdrawal (PBO SC) for 52 weeks. Outcomes assessed were normalisation of hs-CRP and FCP concentrations at week 12 of induction and at week 52 of maintenance in patients with elevated biomarkers at baseline (hs-CRP &amp;gt; 5 mg/L and/or FCP &amp;gt; 250 μg/g), clinical biomarker response (defined as enhanced clinical response [≥ 60% average daily stool frequency (SF) decrease and/or ≥ 35% average daily abdominal pain score (APS) decrease] and ≥ 50% reduction in hs-CRP or FCP), and clinical biomarker remission (defined as clinical remission per CD Activity Index or SF/APS criteria and normal hs-CRP or FCP) during maintenance treatment. Nonresponder imputation was used for missing data. Results Greater proportions of patients receiving RZB vs PBO achieved normalisation of hs-CRP and FCP at the end of the 12-week induction period and the 52-week maintenance period (P &amp;lt; .0001 for all; Table). Among patients with clinical response to RZB IV induction and entered maintenance, rates of clinical biomarker response were maintained through week 52 in patients receiving 360 mg RZB SC and declined over time among patients in the withdrawal (PBO SC) arm (Figure A). Rates of clinical biomarker remission increased over time in patients receiving 360 mg RZB SC. At week 52, clinical remission and normalisation of hs-CRP or FCP was achieved by 41% of patients receiving RZB vs 28%–29% of patients in the withdrawal (PBO SC) arm (Figure B-C). The safety profile of RZB in CD was previously reported. Conclusion Normalisation of objective biomarkers of inflammation in CD was achieved with RZB induction and maintenance therapy. Improvements in both clinical outcomes and biomarker levels were sustained with continuous RZB maintenance therapy and decreased over time in patients discontinuing RZB.

Biomarkers for Clinical Response of Extracorporeal Photopheresis

Biomarkers for Clinical Response of Extracorporeal Photopheresis

DOP88 Effect of risankizumab on patient-reported outcomes in patients with Crohn’s Disease who had an inadequate response or intolerance to conventional and/or biologic treatments: Results from phase 3 MOTIVATE and ADVANCE trials

Abstract Background Risankizumab (RZB), an IL-23 inhibitor, is being investigated for Crohn’s disease (CD). MOTIVATE (NCT03105128) and ADVANCE (NCT03104413) were two double-blind, randomised, placebo (PBO)-controlled phase 3 trials evaluating the efficacy and safety of RZB as induction therapy for CD after inadequate response or intolerance to biologic treatment, or conventional or biologic treatment. We investigated the effect of RZB on patient-reported outcomes (PROs) in these two trials. Methods Patients with moderately to severely active CD (CD activity index of 220–450, Simple Endoscopic Score for CD excluding the narrowing component ≥ 6 or ≥ 4 for isolated ileal disease, and average daily stool frequency ≥ 4 and/or average daily abdominal pain score ≥ 2) were randomised 1:1:1 (MOTIVATE; N=569) or 2:2:1 (ADVANCE; N=850) to intravenous RZB 600 mg, RZB 1200 mg or PBO at Weeks 0, 4 and 8. PROs assessed were Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Health Survey (SF 36). Least-squares mean change from baseline to Week 4 and 12 were assessed for each PRO. Additionally, the proportion of patients achieving IBDQ remission (IBDQ total score ≥ 170 points) was evaluated. Comparisons between RZB dosage groups and PBO were based on Cochran-Mantel-Haenszel or chi-square/Fisher’s exact tests; missing data were reported using non-responder imputation. Results In the MOTIVATE (100% biologic inadequate responder [bio-IR]) and ADVANCE (57% bio-IR) trials, significant (P&amp;lt;0.05) improvements in nearly all PROs evaluated were seen as early as Week 4 (Figures 1–4). At Week 12, significant improvements in all PROs were reported for both doses of RZB compared with PBO in both trials, except for the SF-36 Mental Component Summary score (RZB 1200 mg in MOTIVATE), which improved, but not significantly. In MOTIVATE, at Week 4 and 12, IBDQ remission was achieved by significantly (P&amp;lt;0.05) more patients taking RZB (600 mg, 25.1%/38.3%; RZB 1200 mg, 31.9%/44.6%) than PBO (15.5%/26.8%). Results were similar in ADVANCE: RZB 600 mg 30.9%/44.5%, RZB 1200 mg 33.7%/51.5%, and PBO 18.4%/29.8% at weeks 4 and 12, respectively (P&amp;lt;0.001 for both RZB groups compared to PBO). Conclusion Patients with active CD and an inadequate response to conventional or biologic treatment who received RZB (600 mg or 1200 mg) induction therapy reported significant improvements in disease-specific (IBDQ) and general health-related PROs (FACIT and SF-36) compared with PBO, with improvements seen as early as Week 4. Funding statement: Study was funded by AbbVie. Acknowledgement: Medical writing support was provided by Joann Hettasch of Fishawack Facilitate Ltd, and was funded by AbbVie.

S0705 Evaluation of Symptom Improvement During Induction in Patients With Crohn's Disease Treated With Mirikizumab

INTRODUCTION: Mirikizumab (miri), a humanized, IgG4 monoclonal antibody that targets IL23, has shown efficacy and safety in patients treated for Crohn's disease (CD), psoriasis, and ulcerative colitis. In a phase 2, randomised, parallel-arm, placebo-controlled study, symptom improvement was evaluated in patients with moderately-to-severely active CD after intravenous induction treatment with miri (NCT02891226). METHODS: Entry criteria for enrollment included an average daily stool frequency (SF; ≥ 4) and/or the average daily occurrence of abdominal pain (AP; ≥ 2) from the Crohn's Disease Activity Index (CDAI), and a Simple Endoscopic Score for CD ≥ 7 in patients with ileal-colonic or ≥ 4 in patients with isolated ileal disease. Patients were randomised 2:1:1:2 to receive intravenous miri (200 mg, 600 mg, or 1,000 mg) or placebo at weeks 0, 4, and 8. Endpoints in this analysis included changes from baseline in CDAI, SF, and AP at weeks 4, 8, and 12. A mixed effects model for repeated measures analysis was conducted to compare mean changes from baseline across treatment groups for the all-patient cohort and for the biologic-experienced sub-group. Factors in the analysis included treatment, geographic region, baseline score, prior biologic CD therapy (all-patient cohort), visit, and treatment by visit interaction as fixed effects. An unstructured variance covariance was used. RESULTS: A total of 191 patients were randomised at baseline, which included biologic naïve (n = 71) and biologic-experienced patients (n = 120). Changes in CDAI, SF, AP at weeks 4, 8 and 12 compared to baseline are shown in the Table. In the all-patient cohort, statistically significant improvement in CDAI was observed with miri 600 mg and in SF with miri 200 mg compared to placebo as early as week 4 (Table). Improvement in CDAI and SF occurred with all miri doses (200 mg, 600 mg, 1,000 mg) at weeks 8 and 12 and in AP at weeks 8 and 12 with all miri doses. Compared to placebo, the subgroup of biologic-experienced patients showed statistically significant improvement in CDAI at week 4 (miri 600 mg) and at weeks 8 and 12 with all three doses. Further, significant improvement was observed in SF at week 12 (miri 600 mg and miri 1,000 mg) and in AP at week 8 (miri 600 mg) and week 12 (miri 600 mg and miri 1,000 mg). CONCLUSION: Treatment with miri induced early improvement in clinical symptoms and disease activity in patients with moderately-to-severely active CD.Table 1: Treatment Effect of Mirikizumab vs Placebo in Reducing Crohn's Disease Activity Index, Stool Frequency, and Abdominal Pain Over Time

P687 Early and sustained improvement in stool frequency and rectal bleeding following 52 weeks of mirikizumab treatment

Abstract Background Interleukin (IL)-23 is a key cytokine in inflammatory bowel disease pathogenesis. Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in patients with moderate-to-severely active ulcerative colitis (UC) during 52 weeks of a Phase 2 randomised clinical trial (AMAC, NCT02589665). The effects of miri on stool frequency (SF) and rectal bleeding (RB) through Week 52 are reported. Methods Patients (Mayo score 6–12 with endoscopic subscore [ES] ≥2) were randomised 1:1:1:1 to receive intravenous (IV) placebo (n = 63), miri 50 mg (n = 63) or 200 mg (n = 62) with possibility of exposure-based (EB) dose increases, or fixed miri 600 mg (n = 61) every 4 weeks (Q4W). Responders to miri at Week 12 (9-point Mayo score decrease ≥2 points and ≥35% change from baseline, with RB=0 or 1 or decrease ≥1) were re-randomised 1:1 into a double-blind maintenance period to receive miri 200 mg subcutaneously (SC) Q4W (n = 47) or every 12 weeks (Q12W; n = 46), and were treated through Week 52. Patients reported UC symptoms, including SF and RB, via a daily diary. Changes from baseline in average Mayo SF and RB subscores at Weeks 2, 4, and 12 were analysed using a mixed model repeated-measures method to account for missingness and baseline characteristics. Results Significant improvement in SF was observed as early as Week 2 in the miri 600 mg Q4W group and as early as Week 4 in the miri 200 mg Q4W group (Figure). Similarly, significant improvement in RB was observed as early as Week 2 in both the miri 200 mg Q4W and 600 mg Q4W groups. Patients who received miri 200 mg Q4W or 600 mg Q4W had a significantly greater reduction in both SF and RB compared with placebo at Week 12 (all p &amp;lt; 0.001) (Figure). Patients who achieved clinical response at Week 12 and were treated with miri 200 mg SC Q4W or SC Q12W maintained a low average SF and RB score at Week 52. Conclusion Significant improvements in SF and RB occurred as early as Week 2 of induction treatment and continued to improve during maintenance treatment with mirikizumab. These data demonstrate the early efficacy and longer-term effects of an IL-23p19 antibody on these patient-reported outcomes.

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.

689 Early Improvement After Intravenous Ustekinumab Induction in Patients With Ulcerative Colitis: Results From the UNIFI Induction Trial

INTRODUCTION: The UNIFI induction study evaluated the efficacy and safety of ustekinumab (UST) in patients with moderately to severely active ulcerative colitis (UC) after a single intravenous infusion. In this analysis, we evaluated the rapidity of the onset of the treatment effect. METHODS: Eligible patients were randomly assigned to placebo (PBO) or UST 130 mg or ∼6 mg/kg. Patients recorded stool frequency and categorized rectal bleeding daily for the 7 days before each visit. Partial Mayo scores were calculated at baseline and Week 2 using the average of the stool frequency and rectal bleeding scores from the most recent consecutive 3-day period before the visit and the physician's global assessment score recorded at the visit. C-reactive protein (CRP) and fecal biomarkers were measured at baseline and Day 14. RESULTS: At baseline, the mean 3-day average daily stool frequency was 7.0 in the PBO group, 6.9 in the UST 130-mg group, and 7.0 in the UST ∼6-mg/kg group. Patients receiving UST showed greater reductions in the daily number of stools compared with PBO as soon as the first assessment time point at Day 7. Mean changes from baseline in daily stool frequency were -0.7 for PBO, -1.0 for UST 130-mg (P = 0.098), and -1.2 for UST ∼6-mg/kg group (P = 0.018) by Day 7, respectively, and -0.9, -1.6 (P &lt; 0.001), and -1.9 (P &lt; 0.001) by Day 13, respectively (Figure 1). Rectal bleeding scores at baseline and Week 2 are summarized in Figure 2. Patients receiving UST showed significantly greater improvement from baseline to Day 14 in partial Mayo score and CRP (Table, P &lt; 0.001 for all comparisons of UST vs PBO). Differences between the UST and PBO treatment groups in mean changes from baseline to Day 14 in fecal calprotectin did not reach significance (PBO -33.96 mg/kg, UST 130 mg 79.12 mg/kg [P = 0.875], UST ∼6 mg/kg -412.68 mg/kg [P = 0.152]). However, patients receiving UST showed significantly greater improvement in fecal calprotectin at Week 4 (mean changes from baseline: PBO -226.78 mg/kg, UST 130 mg -881.22 mg/kg [P = 0.013], UST ∼6 mg/kg -802.75 mg/kg [P &lt; 0.001]). Similar results were observed for fecal lactoferrin. CONCLUSION: The effect of UST began rapidly after induction, with symptomatic improvement and reduction of systemic inflammation seen as early as the first assessments at Days 7 and 14, respectively.

Intestinal Hyperpermeability in Gulf War Veterans With Chronic Gastrointestinal Symptoms.

Well over 700,000 United States military personnel participated in the Persian Gulf War in which they developed chronic health disorders of undetermined etiology. Up to 25% of Veterans had persistent and chronic gastrointestinal (GI) symptoms, which they suspected were related to their military service in the Gulf. The overall aim of the current study was to evaluate intestinal permeability in previously deployed Gulf War Veterans who developed chronic GI symptoms during their tour in the Persian Gulf. To accomplish this, we evaluated intestinal permeability (IP) using the urinary lactulose/mannitol test. Measurements of intestinal permeability were then correlated with mean ratings of daily abdominal pain, frequency of bowel movements, and consistency of bowel movements on the Bristol Stool Scale in all Veterans. A total of 73 veterans had documented chronic GI symptoms (diarrhea, abdominal pain) and were included in the study. A total of 29/73 (39%) of veterans has increased IP and had a higher average daily stool frequency (P<0.05); increased liquid stools as indicated by a higher Bristol Stool Scale (P<0.01); and a higher mean M-VAS abdominal pain rating (P<0.01). Pearson correlation coefficients revealed that there was a positive correlation between increased IP and stool frequency, Bristol Stool Scale, and M-VAS abdominal pain rating. Our study demonstrates that deployed Gulf War Veterans with persistent GI symptoms commonly have increased intestinal permeability that potentiates the severity of abdominal pain, diarrhea, and stool consistency. These new findings in our study are important as they may lead to novel diagnostic biomarkers for returning Gulf War Veterans who suffer from chronic functional gastrointestinal disorders. These advances are also important for an increasing number of veterans who are now serving in the Persian Gulf and are at a high risk of developing these chronic pain disorders.

Effects of Conventional Milk Versus Milk Containing Only A2 β-Casein on Digestion in Chinese Children: A Randomized Study.

ABSTRACTObjectives:In this study, we hypothesized that replacing conventional milk, which contains A1 and A2 β-casein proteins, with milk that contains only A2 β-casein in the diet of dairy or milk-intolerant preschoolers (age 5 to 6 years) would result in reduced gastrointestinal symptoms associated with milk intolerance, and that this would correspond with cognitive improvements.Methods:This randomized, double-blind, crossover study aimed to compare the effects of 5 days’ consumption of conventional milk versus milk containing only A2 β-casein on gastrointestinal symptoms, as assessed via visual analog scales, average stool frequency and consistency, and serum inflammatory and immune biomarkers in healthy preschoolers with mild-to-moderate milk intolerance. The study also aimed to compare changes in the cognitive behavior of preschoolers, based on Subtle Cognitive Impairment Test scores.Results:Subjects who consumed milk containing only A2 β-casein had significantly less severe gastrointestinal symptoms as measured by visual analog scales, reduced stool frequency, and improvements in stool consistency, compared with subjects consuming conventional milk. There were significant increases from baseline in serum interleukin-4, immunoglobulins G, E, and G1, and beta-casomorphin-7 coupled to lower glutathione levels, in subjects consuming conventional milk compared with milk containing only A2 β-casein. Subtle Cognitive Impairment Test analysis showed significant improvements in test accuracy after consumption of milk containing only A2 β-casein. There were no severe adverse events related to consumption of either milk product.Conclusions:Replacing conventional milk with milk containing only A2 β-casein reduced gastrointestinal symptoms associated with milk intolerance in Chinese preschool children, with corresponding improvements in aspects of cognitive performance.

Mixture model analysis identifies irritable bowel syndrome subgroups characterised by specific profiles of gastrointestinal, extraintestinal somatic and psychological symptoms.

Current subgrouping of Irritable Bowel Syndrome (IBS) is exclusively based on stool consistency without considering other relevant gastrointestinal (GI), extraintestinal somatic or psychological features. To identify subgroups based on a comprehensive set of IBS-related parameters. Mixture model analysis was used, with the following input variables: 13 single-item scores from the IBS-specific Gastrointestinal Symptom Rating Scale, average stool consistency and frequency from a 7-day Bristol Stool Form diary, 12 single-item extraintestinal symptom scores from the Patient Health Questionnaire-12, and anxiety and depression subscale scores from the Hospital Anxiety and Depression scale. The resulting latent subgroups were compared regarding symptom profiles using analysis of variance followed by pair-wise comparisons. One hundred and seventy-two IBS patients (Rome III; 69% female; mean age 33.7 [range 18-60] years) were included. The optimal subgrouping showed six latent groups, characterised by: (I) constipation with low comorbidities, (II) constipation with high comorbidities, (III) diarrhoea with low comorbidities, (IV) diarrhoea and pain with high comorbidities, (V) mixed GI symptoms with high comorbidities, (VI) a mix of symptoms with overall mild severity. The subgroups showed differences in the distribution of Rome III-subtypes, IBS severity, presence of anxiety and depression, and gender, but not regarding age, IBS duration or reported post-infectious onset of IBS. This model-based subgrouping of IBS partly supports the distinction of subgroups based on bowel habits, but additionally distinguishes subgroups with or without co-morbid extraintestinal somatic and psychological symptoms. The resulting groups show specific profiles of symptom combinations.

Prebiotics for the management of hyperbilirubinemia in preterm neonates

Objective: We evaluated if prebiotics have benefits for the management of hyperbilirubinemia in preterm neonates.Methods: Preterm neonates were entered into the study when enteral feeding volume met 30 mL/kg/day. They randomly received a mixture of short-chain galacto-oligosacarids/long-chain fructo-oligosacarids or distilled water (placebo) for 1 week. Total serum bilirubin level was measured by transcutaneous bilirubinometry. Stool frequency and meeting full enteral feeding during the study period were considered as secondary outcomes.Results: Twenty-five neonates in each group completed the trial. Bilirubin level was decreased with the prebiotic (−1.3 ± 1.8 mg/dL, p = 0.004), but not placebo (−0.1 ± 3.3 mg/dL, p = 0.416). Peak bilirubin level was lower with the prebiotic than placebo (8.3 ± 1.7 versus 10.1 ± 2.2 mg/dL, p = 0.003). Stool frequency was increased with the prebiotic (0.7 ± 1.9 defecation/day, p = 0.014), but not with placebo (0.6 ± 1.5 defecation/day, p = 0.133). Average stool frequency (2.4 ± 0.4 versus 1.9 ± 0.5 defecation/day, p = 0.003) and frequently of meeting full enteral feeding (60% versus 16%, p = 0.002) were higher with the prebiotic than placebo.Conclusions: Prebiotic oligosaccharides increase stool frequency, improve feeding tolerance and reduce bilirubin level in preterm neonates and therefore can be efficacious for the management of neonatal hyperbilirubinemia.

Associations of Clinical Symptoms and Bowel Characteristics With Intestinal Microbiota in Patients With Irritable Bowel Syndrome: ACG Governors Award for Excellence in Clinical Research

Introduction: The intestinal microbiota has been suggested as an important factor in the pathogenesis of IBS. However, most of the studies characterizing the intestinal microbiota in IBS focused on IBS diagnosis and its subtypes as defined by the Rome criteria. The associations between the intestinal microbiota, specific IBS symptoms and altered bowel habits have not been adequately investigated. Aim: To investigate the relationship between the intestinal microbiota, IBS-related GI symptoms and bowel characteristics. Methods: Fresh fecal samples were collected from IBS patients (Rome III criteria) and healthy controls (HC). Clinical variables included severity and frequency of abdominal pain, abdominal bloating and IBS symptom severity (IBS-SSS). Bowel characteristics were assessed by average daily stool frequency and consistency. The intestinal microbiota was investigated by phylogenetic microarray analysis. Analysis was done using linear models and correlation analyses were done using Spearman's (for ordinal data) and Pearson (for continuous data) coefficients both with Benjamini-Hochberg false discovery rate (FDR) correction for multiple comparisons. Random forest analysis (Breiman 2001) was carried out for selection of the bacteria most contributing to the outcome. Results: A total of 83 IBS patients and 24 HC were investigated. We found significant associations (p < 0.05) between specific bacterial taxa and several clinical variables. For example, several Bacteroides groups correlated positively with pain and negatively with IBS-QOL. In contrary Bifidobacteria correlated negatively with IBS severity and positively with IBS-QOL. Random forest analysis showed a set of 5 bacterial groups that explain 33% of variation in stool consistency (Clostridium leptum, Papillibacter cinnamivorans Faecalibacterium prausnitzii, Clostridium stercorarium and Akkermansia) and 3 bacterial groups that explain 23% of the variance in stool frequency (Clostridium ramosum, Prevotella melaninogenica, and Papillibacter cinnamivorans) (Figure 1).Figure 1Conclusion: Subjective reports of specific clinical symptoms and altered bowel characteristics are associated with significant alterations in the composition of the intestinal microbiota. However, our findings indicate that the microbial alterations associated with clinical symptoms and bowel characteristics are different, thus suggesting a complex multifactorial role of the intestinal microbiota in the clinical experience of IBS.