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Treatment of IBS diarrhoea

Peter Whorwell 1

Affiliations

1 University of Manchester Wythenshawe Hospital, Manchester, United Kingdom

Summary

AI Generated

The speaker presents a practical approach to managing IBS with diarrhoea, emphasizing dietary modification, strategic use of antidiarrheals and other medications, and behavioural therapies for patients not responding to first-line treatment.

Diet is critically important in IBS; the speaker reported that 55% of patients were made worse by bran in his study, and recommends combining a low FODMAP diet with elimination of cereal fibre such as bran, Weetabix, and brown bread for better results.
Loperamide can be dosed as a quarter or half capsule 3 to 4 times daily to avoid constipation and works better than a single full dose, though it does not help pain and can be combined with antispasmodics.
Ondansetron is effective for IBS-D and can be used regularly or as needed; it has useful antiemetic activity since the speaker noted 70 to 80% of IBS patients report nausea.
Eluxadoline improved both pain and bowel function and was described by the speaker as life-changing for some tertiary-care patients, but has been withdrawn in Europe and the UK due to pancreatitis concerns and is contraindicated in liver disease.
Low-dose tricyclic antidepressants such as amitriptyline at 10 mg are very useful for IBS; the speaker emphasizes explaining to patients that the low dose is for gut effects, not depression.
Gut-focused hypnotherapy and cognitive behavioural therapy have good evidence in IBS, and the speaker stated that hypnotherapy can change the physiology of the gut.

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Abstract

Event

UEG Week Vienna 2024

Topics

Hepatobiliary Paediatrics Primary Care

Session

When things get shitty: Diarrhoea

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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LINKING INCREASED COLONIC PERMEABILITY WITH AN ALTERED BLOOD-BRAIN BARRIER AND PRESENCE OF NEUROINFLAMMATION IN A RAT MODEL FOR DISORDERS OF GUT-BRAIN INTERACTION

Ricard Farré

MICROBIAL DYSBIOSIS, INFLAMMATION, AND THE GUT-BRAIN AXIS IN IRRITABLE BOWEL SYNDROME: INSIGHTS FROM THE DISCOVERIE COHORT

Dan Lucian Dumitrascu

Intestinal microbiome

Elena Verdu

DEVELOPMENT OF A DE NOVO CLINICAL OUTCOME ASSESSMENT FOR CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

Valeria Scuderi

Pathophysiology: Microbiota T-2D and MASLD

Onno Holleboom

TWO YEAR RESULTS OF SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) DOSE ESCALATION THERAPY AS AN OPTION FOR MANAGING LOSS OF RESPONSE IN INFLAMMATORY BOWEL DISEASE – FROM LIBERTY-UC AND LIBERTY-CD STUDY

Sun Hee Lee

UEG Presentation

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LINKING INCREASED COLONIC PERMEABILITY WITH AN ALTERED BLOOD-BRAIN BARRIER AND PRESENCE OF NEUROINFLAMMATION IN A RAT MODEL FOR DISORDERS OF GUT-BRAIN INTERACTION

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LINKING INCREASED COLONIC PERMEABILITY WITH AN ALTERED BLOOD-BRAIN BARRIER AND PRESENCE OF NEUROINFLAMMATION IN A RAT MODEL FOR DISORDERS OF GUT-BRAIN INTERACTION

Alice Rustichelli 1, Sybren Rinckhout 1, Luigi Musetta 2, Bram Callewaert 2, Silvia Pinto 3, Tim Vanuytsel 1, Jan Tack 1, Rudi Vennekens 3, Uwe Himmelreich 2, Ricard Farré 1

Affiliations

1 KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium

2 KU Leuven, Biomedical MRI unit/ MoSAIC, Leuven, Belgium

3 KU Leuven, Laboratory of Ion Channel Research, Leuven, Belgium

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Abstract

Introduction

Irritable bowel syndrome (IBS) is defined as a disorder of gut-brain interaction (DGBI) and is characterised by intestinal immune activation, increased intestinal permeability, and structural and functional brain alterations. DGBI patients have a higher prevalence of psychological comorbidities. Nevertheless, the exact pathophysiological link between these factors and the sequence of events is unknown. Gut alterations have been suggested to induce brain neuroinflammation in DGBI, but scientific evidence is lacking.

Aims & Methods

The present study aims to assess whether GI alteration induces brain neuroinflammation, alters brain function, and, consequently, induces psychological comorbidities. A unique longitudinal study was conducted from 30 to 220 days of age to establish the chronological sequence of intestinal and neurological changes. For this, we utilised the BioBreeding diabetes-prone (BBDP) rat model, which spontaneously develops intestinal inflammation, increased permeability, and colonic hypersensitivity^{1, 2}and has been employed as a model of DGBI. The BioBreeding diabetes-resistant (BBDR) was used as control. Anxiety-like behaviour was assessed using the elevated plus maze. Intestinal permeability was assessed in vivo by measuring the passage of 4 kDa and 70 kDa dextrans into the blood, thereby evaluating paracellular and transcellular permeability, respectively. The appearance of red colour, given by the mixture of the dextrans in the stools, was used to assess overall intestinal motility. The blood-brain barrier (BBB) integrity and brain metabolic profile were assessed using contrast-enhanced magnetic resonance imaging (0.25 mL/100g weight of 0.05 mM, gadolinium) and proton magnetic resonance spectroscopy, respectively.

Results

BBDP rats exhibit an increased colonic permeability starting from 90 days, and reduced GI motility at 90 and 160 days. Interestingly, this increased permeability is accompanied by an increased BBB permeability at 220 days only in the anterior cingulate cortex (ACC) but not in the hippocampus, insula, amygdala, or thalamus. BBDP rats showed a slight increase in total choline and myoinositol concentrations in the ACC and the insula at late time points, which may indicate increased neuroinflammation. BBDP rats also have higher concentrations of glutamine-glutamate in the insula and N-acetyl aspartate in the ACC. Moreover, BBDP rats develop anxiety-like behaviour at 160 and 220 days.

Conclusion

The BBDP rat model supports the current hypothesis that increased gut permeability can lead to brain neuroinflammation, altered function, and, consequently, to psychological comorbidities.
EU-funded DISCOvERIE project (No. 848228).

References

1. Meleine M, Accarie A, Wauters L, et al. Colonic hypersensitivity and low-grade inflammation in a spontaneous animal model for functional gastrointestinal disorders. Neurogastroenterol Motil 2019;31:e13614.
2. Vanuytsel T, Vanormelingen C, Vanheel H, et al. From intestinal permeability to dysmotility: the biobreeding rat as a model for functional gastrointestinal disorders. PLoS One 2014;9:e111132.

Event

UEG Week Berlin 2025

Topics

Neurogastroenterology & Motility Colorectal

Submission format

Abstract

Session

Lower GI motility III

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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LINKING INCREASED COLONIC PERMEABILITY WITH AN ALTERED BLOOD-BRAIN BARRIER AND PRESENCE OF NEUROINFLAMMATION IN A RAT MODEL FOR DISORDERS OF GUT-BRAIN INTERACTION

Ricard Farré

MICROBIAL DYSBIOSIS, INFLAMMATION, AND THE GUT-BRAIN AXIS IN IRRITABLE BOWEL SYNDROME: INSIGHTS FROM THE DISCOVERIE COHORT

Dan Lucian Dumitrascu

Intestinal microbiome

Elena Verdu

DEVELOPMENT OF A DE NOVO CLINICAL OUTCOME ASSESSMENT FOR CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

Valeria Scuderi

Pathophysiology: Microbiota T-2D and MASLD

Onno Holleboom

TWO YEAR RESULTS OF SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) DOSE ESCALATION THERAPY AS AN OPTION FOR MANAGING LOSS OF RESPONSE IN INFLAMMATORY BOWEL DISEASE – FROM LIBERTY-UC AND LIBERTY-CD STUDY

Sun Hee Lee

UEG Presentation

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MICROBIAL DYSBIOSIS, INFLAMMATION, AND THE GUT-BRAIN AXIS IN IRRITABLE BOWEL SYNDROME: INSIGHTS FROM THE DISCOVERIE COHORT

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MICROBIAL DYSBIOSIS, INFLAMMATION, AND THE GUT-BRAIN AXIS IN IRRITABLE BOWEL SYNDROME: INSIGHTS FROM THE DISCOVERIE COHORT

Jorge Francisco Vazquez Castellanos 1, Jeroen Raes 1, Javier Santos 2, Amanda Rodriguez 2, Maaike Van Den Houte 3, Dan Lucian Dumitrascu 4, Andrei Pop 5, Jekkel Eva 6, Giovanni Barbara 7, Maria Raffaella Barbaro 8, Magnus Simrén 9, Irina Midenfjord 10, Danique Mulder 11, Michelle Bosman 12, Daisy Mae Jonkers 13, Mareike Aichholzer 14, Juan Garcia 2, Carmen Alonso-Cotoner 15, Stefanie Schmitteckert 16, Arno Lukas 17, Ricardo Brandwijk 18, Lindsey De Commer 1, Muriel Derrien 1, Lindsay Devolder 1, Chloë Verspecht 1, Iris Reniers 1, Ami De Weerdt 1, Daniel Ekhlas 1, Jan Tack 19, Lukas Van Oudenhove 20, Ricard Farré Marti 3, John F. Cryan 21, Gerard Clarke 22

Affiliations

1 KU-Leuven/VIB, Leuven, Belgium

2 Institut de Recerca Vall d`Hebron, Barcelona, Spain

3 KU Leuven, Leuven, Belgium

4 University of Medicine and Pharmacy, Cluj-Napoca, Romania

5 Iuliu Hatieganu University of Medicine and Pharmacy, ClujNapoca, Romania

6 Semmelweis University, Budapest, Hungary

7 University of Bologna, Bologna, Italy

8 University of Bologna Dept. of Medical and Surgical Sciences, Bologna, Italy

9 Sahlgrenska University Hospital - Dept of Internal Medicine, Sahlgrenska University Hospital ; Gothe, Gothenburg, Sweden

10 Institute of Medicine, Gothenburg, Sweden

11 Radboud University Medical Center, Nijmegen, Netherlands

12 Maastricht University Medical Center +, Venlo, Netherlands

13 Maastricht University Medical Center - Department of Internal Medicine, Division of Gastroenterology, Maastricht, Netherlands

14 Goethe University, University Hospital, Frankfurt, Germany

15 Hospital Val Hebron, Barcelona, Spain

16 University Hospital Heidelberg, Heidelberg, Germany

17 emergenTec, Vienna, Austria

18 Hycult Biotech, Uden, Netherlands

19 University of Leuven, University Hospital Gasthuisberg, Leuven, Belgium

20 Katholieke Universiteit Leuven, Leuven, Belgium

21 University College Cork, Cork, Ireland

22 g.clarke@ucc.ie, Corke, Ireland

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Abstract

Introduction

Irritable Bowel Syndrome (IBS) is a prevalent and chronic gastrointestinal disorder that affects approximately 85 million Europeans. It predominantly impacts women and significantly impairs quality of life, presenting with recurrent abdominal pain and altered bowel habits in the absence of identifiable structural abnormalities. Beyond its gastrointestinal symptoms, IBS frequently co-occurs with mental and somatic conditions such as anxiety, depression, fibromyalgia (32.5%), and chronic fatigue syndrome (14%). Up to 60% of IBS patients experience mental comorbidities, highlighting the complex interplay between gut and brain—often referred to as dysregulation of the gut–brain axis. This dysregulation manifests in altered intestinal motility, increased gut permeability, visceral hypersensitivity, and significant shifts in gut microbiota composition.

Aims & Methods

We present the DISCOVERIE project (Development, dIagnostic and prevention of gender-related Somatic and mental COmorbitiEs in iRritable bowel syndrome In Europe), an international, multi-centre initiative aimed at characterizing IBS and its associated comorbidities, with a particular focus on sex- and gender-related differences. To this end, we generated a comprehensive multi-omics dataset from 743 individuals, including shotgun quantitative microbiome profiling and untargeted metabolomics. These molecular data were complemented by in-depth clinical phenotyping, capturing information on anxiety, depression, fibromyalgia, and chronic fatigue syndrome. Particular attention was given to age, sex/gender, lifestyle factors, and systemic inflammatory markers. Multivariate statistical models were applied, correcting for common microbiome confounders, to analyze the multi-omics layers and identify microbiome-related signatures and mechanistic links across IBS and its comorbid subgroups.

Results

Our microbiome analysis revealed that IBS subjects exhibit features of a dysbiotic bacterial community, characterized by an increased prevalence of the Bacteroides 2 enterotype (17–26% in IBS participants across comorbid groups vs. 17% in the general population and only 2% in the healthy control group; chi-squared test, FDR < 0.05), a reduced butyrate synthesis capacity, and increased levels of opportunistic taxa compared to non-IBS controls.
Interestingly, IBS individuals—regardless of comorbidities—showed enrichment of bacterial metabolic modules involved in the degradation of amino acids that serve as precursors for neurotransmitters. Specifically, we observed an increase in pathways associated with GABA degradation and a decrease in modules responsible for glutamate biosynthesis. This dysregulation of gut neurotransmitter metabolism may contribute to hallmark IBS symptoms.
Strikingly, pro-inflammatory IL-6 levels were strongly associated with specific bacterial genus (FDR < 0.05), as well as with a metabolic module responsible for the degradation of gamma-hydroxybutyric acid (GHB), a neurotransmitter and central nervous system depressant, suggesting a potential mechanistic link between low-grade inflammation and depressive symptoms in IBS.

Conclusion

The results from this large-scale, multi-center international study reveal a dysregulation of gut neurotransmitter metabolism that may contribute to IBS symptoms and associated comorbidities. These findings underscore a potential link between elevated IL-6 levels, microbial metabolism, and the gut–brain axis, offering new insights into the complex interplay between microbiota composition, host physiology, and IBS-related comorbidities.

Event

UEG Week Berlin 2025

Topics

Gut Microbiota IBD Colorectal

Submission format

Abstract

Session

New tales of the gut microbiome: From profiling to new therapies

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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LINKING INCREASED COLONIC PERMEABILITY WITH AN ALTERED BLOOD-BRAIN BARRIER AND PRESENCE OF NEUROINFLAMMATION IN A RAT MODEL FOR DISORDERS OF GUT-BRAIN INTERACTION

Ricard Farré

MICROBIAL DYSBIOSIS, INFLAMMATION, AND THE GUT-BRAIN AXIS IN IRRITABLE BOWEL SYNDROME: INSIGHTS FROM THE DISCOVERIE COHORT

Dan Lucian Dumitrascu

Intestinal microbiome

Elena Verdu

DEVELOPMENT OF A DE NOVO CLINICAL OUTCOME ASSESSMENT FOR CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

Valeria Scuderi

Pathophysiology: Microbiota T-2D and MASLD

Onno Holleboom

TWO YEAR RESULTS OF SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) DOSE ESCALATION THERAPY AS AN OPTION FOR MANAGING LOSS OF RESPONSE IN INFLAMMATORY BOWEL DISEASE – FROM LIBERTY-UC AND LIBERTY-CD STUDY

Sun Hee Lee

UEG Presentation

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Intestinal microbiome

Elena Verdu 1

Affiliations

1 McMaster University, Hamilton, Canada

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Abstract

Event

UEG Week Vienna 2024

Topics

Endoscopy Gut Microbiota IBD Oesophagus Stomach & H. Pylori

Session

Best of DDW

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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LINKING INCREASED COLONIC PERMEABILITY WITH AN ALTERED BLOOD-BRAIN BARRIER AND PRESENCE OF NEUROINFLAMMATION IN A RAT MODEL FOR DISORDERS OF GUT-BRAIN INTERACTION

Ricard Farré

MICROBIAL DYSBIOSIS, INFLAMMATION, AND THE GUT-BRAIN AXIS IN IRRITABLE BOWEL SYNDROME: INSIGHTS FROM THE DISCOVERIE COHORT

Dan Lucian Dumitrascu

Intestinal microbiome

Elena Verdu

DEVELOPMENT OF A DE NOVO CLINICAL OUTCOME ASSESSMENT FOR CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

Valeria Scuderi

Pathophysiology: Microbiota T-2D and MASLD

Onno Holleboom

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Sun Hee Lee

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

DEVELOPMENT OF A DE NOVO CLINICAL OUTCOME ASSESSMENT FOR CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

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DEVELOPMENT OF A DE NOVO CLINICAL OUTCOME ASSESSMENT FOR CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

Madhusudan Grover 1, Jan Tack 2, Sara Manzoni 3, Elena Pasquali 3, Valeria Scuderi 3, Vincenzo Stanghellini 4

Affiliations

1 Mayo Clinic, Rochester, MN, United States

2 University Hospitals Leuven, Leuven, Belgium

3 Alfasigma S.p.A., Bologna, Italy

4 IRCCS Sant’Orsola-Malpighi University Hospi, Bologna, Italy

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Abstract

Introduction

Chronic intestinal pseudo-obstruction (CIPO) is a rare disease where impaired propulsive activity of the gut leads to bowel dilatation without an anatomical obstruction. There is no single assessment that comprehensively assesses the severity of symptoms and their impact on patients. Our aim was to develop a CIPO-specific electronic patient-reported outcome (ePRO), the CIPO Daily Diary^© (CIPO eDD), for clinical trials.

Aims & Methods

The CIPO eDD was developed per FDA guidelines^1,2 in a noninterventional, cross-sectional, qualitative interview study. This multi-stage process started with a targeted literature review and GAP analysis, with subsequent input from experts and patients. Literature reviews identified key signs and symptoms, and outcomes previously used in CIPO. Interviews with 3 clinicians experienced in diagnosing and treating CIPO, and insights from a steering committee that included the 3 clinicians and 2 external consultants, identified draft elements for the CIPO eDD. The draft CIPO eDD underwent iterative (4 rounds) hybrid concept elicitation (CE)/cognitive interviews and usability testing (CIUT) with patients from the USA (aged 18–80 years) with physician-confirmed CIPO diagnosis. For CE, patients answered open-ended questions about their CIPO experiences. CIPO signs, symptoms and impacts (concepts) emerged spontaneously from the responses. For CIUT, patients completed the CIPO eDD and reviewed the comprehensiveness, relevance and clarity of items. Textual analysis of interview transcripts guided amendments to the CIPO eDD items based on patient feedback. Following the initial CE/CIUT interviews, the same patients answered follow-up questions about the draft CIPO eDD to refine the items and to obtain qualitative and preliminary quantitative evidence for the potential revision or removal of items.

Results

Overall, 14 patients (female, n=10; mean [SD] age and time since diagnosis, 55.3 [15.5] and 4.3 [4.0] years, respectively) were interviewed. Concept saturation was reached after 3 rounds of CE/CIUT, with 15 of the 25 unique CIPO signs and symptoms included in the CIPO eDD (Table). Based on feedback from follow-up interviews (12 patients), no changes were made to items in the draft CIPO eDD. Minor changes were made to four items (vomiting, regurgitation, early satiety and CIPO episodes) suggested by qualitative data and the steering committee to improve clarity; the order of the nausea and vomiting items was switched. The sorting exercise did not identify any items for addition/removal or revision based on the qualitative evidence, with most patients indicating that all items should remain in the diary.

Conclusion

We have developed a de novo CIPO-specific ePRO per established FDA guidelines.^1,2 A final scoring system of the CIPO eDD based on the 15 items is in development. Ongoing quantitative assessment and psychometric validation of the CIPO eDD will enable its use in monitoring CIPO severity in clinical trials, thus supporting the development of effective therapies.

Table. Final items for the CIPO Daily Diary, and amendments from patient interviews

Item	Response type	Revisions	Item	Response type	Revisions
Abdominal pain	Categorical scale from 0 (none) to 4 (very severe)	Amended wording and text formatting	Heartburn	Categorical scale from 0 (none) to 4 (very severe)	Amended wording and text formatting
Bloating	Categorical scale from 0 (none) to 4 (very severe)	Amended wording and text formatting; reordered item	Feeling of food or liquid coming back up	Discrete scale from 0 to 10 or more	Amended wording and text formatting
Distension	Categorical scale from 0 (none) to 4 (very severe)	Removed and re-added; amended text formatting; reordered item	Impaired ability to eat solid food	Categorical scale from 0 (not at all) to 4 (I was not able to eat solid food)	Amended wording and text formatting; separated into a distinct item by specifying ‘solid’ food; reordered item
Bowel movements: number	Discrete scale from 0 to 10 or more	Amended text formatting	Impaired ability to consume liquid food	Categorical scale from 0 (not at all) to 4 (I was not able to consume liquid food)	Amended wording and text formatting; separated into a distinct item by specifying ‘liquid’ food; reordered item
Bowel movements: type	Categorical scale from type 1 (separate hard lumps, like nuts) to type 7 (watery, no solid pieces)	Amended wording and text formatting	Feeling of fullness soon after you started to eat	Categorical scale from 0 (none) to 4 (very severe)	Amended wording and text formatting; reordered item; amended item dependencies
Bowel movements: number of each type	Discrete scale from 0 to 10 or more for each type	Amended text formatting	Feeling of being unpleasantly full, long after you finished eating	Categorical scale from 0 (none) to 4 (very severe)	Amended wording and text formatting; reordered item; amended
Vomiting	Discrete scale from 0 to 10 or more	Amended wording and text formatting	Experience of an acute CIPO episode or continuation of a previous one	Yes, no, I’m not sure	Amended wording and text formatting; reordered item; addition of a definition for CIPO episode
Nausea	Categorical scale from 0 (none) to 4 (very severe)	Amended wording and text formatting
All items are based on a 24-h recall period. Dry heaving, feeling excessively full after a light snack and epigastric pain were removed during interviews. CIPO, chronic intestinal pseudo-obstruction. Copyright 2025 Alfasigma S.p.A.

References

FDA. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-measures-use-medical-product-development-support-labeling-claims (Accessed April 15, 2025).
FDA. Patient-Focused Drug Development: Collecting Comprehensive and Representative Input. 2009. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-collecting-comprehensive-and-representative-input (Accessed April 15, 2025).

Disclosure

MG has received research support from Alexza Pharmaceuticals, Alfasigma, Donga and Takeda; and is an advisory board member for Alfasigma, Ardelyx and Evoke Pharma.
ViS is an advisory board member and/or speaker for Alfasigma, Bayer, Bromatech, Falck and GE Healthcare; and receives research support from Alfasigma.
JT has given scientific advice to Aclipse, Adare Pharma Solutions, Alfasigma, Clasado, Danone, Dr Falk Pharma, FitForMe, Ironwood, Kyowa Kirin, Menarini, PRO.MED.CS, Recordati, Takeda, Truvion Healthcare, Tsumura and Zealand Pharmaceuticals; receives research support from BIOHIT Healthcare, Kyowa Kirin, ProMed, Sofar and Takeda; and is a speaker for Abbott, Biocodex, Mayoly, Menarini, ProMed, Reckitt Benckiser, Schwabe, Takeda, Thai Meiji Pharmaceutical and Truvion Healthcare.
SM, EP and VaS are employees of Alfasigma S.p.A.
This study was sponsored by Alfasigma S.p.A.
The authors would like to thank all of the Alfasigma team who were involved in this study for their contributions to study conceptualization, study design, methodology, data curation, formal analysis, data interpretation and endorsement of the study design. In addition, the authors would like to thank the external consultants for their time and expertise, and the principal investigators at the collaborating sites for patient recruitment and data collection.
Medical writing support for the development of this abstract was provided by Hannah Stephens, PhD, of PharmaGenesis London, London, UK, and was funded by Alfasigma S.p.A.

Event

UEG Week Berlin 2025

Topics

Neurogastroenterology & Motility Colorectal

Submission format

Abstract

Session

Lower GI motility I

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

LINKING INCREASED COLONIC PERMEABILITY WITH AN ALTERED BLOOD-BRAIN BARRIER AND PRESENCE OF NEUROINFLAMMATION IN A RAT MODEL FOR DISORDERS OF GUT-BRAIN INTERACTION

Ricard Farré

MICROBIAL DYSBIOSIS, INFLAMMATION, AND THE GUT-BRAIN AXIS IN IRRITABLE BOWEL SYNDROME: INSIGHTS FROM THE DISCOVERIE COHORT

Dan Lucian Dumitrascu

Intestinal microbiome

Elena Verdu

DEVELOPMENT OF A DE NOVO CLINICAL OUTCOME ASSESSMENT FOR CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

Valeria Scuderi

Pathophysiology: Microbiota T-2D and MASLD

Onno Holleboom

TWO YEAR RESULTS OF SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) DOSE ESCALATION THERAPY AS AN OPTION FOR MANAGING LOSS OF RESPONSE IN INFLAMMATORY BOWEL DISEASE – FROM LIBERTY-UC AND LIBERTY-CD STUDY

Sun Hee Lee

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Pathophysiology: Microbiota T-2D and MASLD

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Pathophysiology: Microbiota T-2D and MASLD

Onno Holleboom 1

Affiliations

1 Amsterdam UMC, Amsterdam, Netherlands

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Abstract

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Gut Microbiota Hepatobiliary Mechanisms & Personalised Medicine

Session

Diabetes in GI disorders

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

LINKING INCREASED COLONIC PERMEABILITY WITH AN ALTERED BLOOD-BRAIN BARRIER AND PRESENCE OF NEUROINFLAMMATION IN A RAT MODEL FOR DISORDERS OF GUT-BRAIN INTERACTION

Ricard Farré

MICROBIAL DYSBIOSIS, INFLAMMATION, AND THE GUT-BRAIN AXIS IN IRRITABLE BOWEL SYNDROME: INSIGHTS FROM THE DISCOVERIE COHORT

Dan Lucian Dumitrascu

Intestinal microbiome

Elena Verdu

DEVELOPMENT OF A DE NOVO CLINICAL OUTCOME ASSESSMENT FOR CHRONIC INTESTINAL PSEUDO-OBSTRUCTION

Valeria Scuderi

Pathophysiology: Microbiota T-2D and MASLD

Onno Holleboom

TWO YEAR RESULTS OF SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) DOSE ESCALATION THERAPY AS AN OPTION FOR MANAGING LOSS OF RESPONSE IN INFLAMMATORY BOWEL DISEASE – FROM LIBERTY-UC AND LIBERTY-CD STUDY

Sun Hee Lee

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

TWO YEAR RESULTS OF SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) DOSE ESCALATION THERAPY AS AN OPTION FOR MANAGING LOSS OF RESPONSE IN INFLAMMATORY BOWEL DISEASE – FROM LIBERTY-UC AND LIBERTY-CD STUDY

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

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TWO YEAR RESULTS OF SUBCUTANEOUS INFLIXIMAB (CT-P13 SC) DOSE ESCALATION THERAPY AS AN OPTION FOR MANAGING LOSS OF RESPONSE IN INFLAMMATORY BOWEL DISEASE – FROM LIBERTY-UC AND LIBERTY-CD STUDY

Stefan Schreiber 1, Jean-Frédéric Colombel 2, Steve Hanauer 3, William Sandborn 4, Bruce E. Sands 2, Silvio Danese 5, SangJoon Lee 6, Sung Hyun Kim 6, Yun Ju Bae 6, Sun Hee Lee 6, Seul Gi Lee 6, JoonHo Lee 6, Jong Min Kim 6, Gahee Park 6, Jimin Lee 6, Juhyun Lee 6

Affiliations

1 University Hospital Schleswig-Holstein, Kiel, Germany

2 Icahn School of Medicine at Mount Sinai, New York, United States

3 Northwestern University/ Feinberg School of Medicine, Chicago, United States

4 University of California San Diego, San Diego, United States

5 Vita-Salute San Raffaele University - IRCCS San Raffaele Scientific Institute, Milan, Italy

6 Celltrion, Inc, Incheon, Korea, Republic of

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Abstract

Introduction

Dose escalation (DE) of intravenous infliximab is an option for inflammatory bowel disease (IBD) patients who lose response after induction therapy^{1, 2}. DE of subcutaneous (SC) infliximab from 120 mg to 240 mg every 2 weeks (Q2W) showed restoring efficacy in the 54-week LIBERTY-UC and LIBERTY-CD studies, and safety profiles were generally comparable between patients with or without DE³. Both two studies included an extension phase through Week (W) 102, and we present post-hoc long-term efficacy and safety results of DE in patients who treated in extension phase in two studies.

Aims & Methods

Patients with moderately to severely active UC and CD were treated with 3 doses of infliximab IV 5mg/kg as induction therapy (Weeks 0, 2 and 6). Clinical responders at W10 were randomized (2:1) to receive either CT-P13 SC 120 mg or placebo Q2W as maintenance therapy up to W54. Patients who, in the opinion of the investigator, would benefit from continued treatment entered open-label extension study from W56 to W102 and received CT-P13 SC 120 mg regardless of previously assigned arm. From W22, the patients who met loss of response criteria were permitted to escalate the dose to CT-P13 SC 240 mg Q2W through W102 for both arms. The results from CT-P13 SC arm are analyzed.

Results

A total of 237 and 180 patients who were randomly assigned to CT-P13 SC 120 mg arm and treated in extension phase in UC and CD study, each. Among them, DE from CT-P13 SC 120 mg to CT-P13 SC 240 mg prior to W102 was more common in UC than CD (30.0% [71/237] vs 20.6% [37/180]). Patients showed improvement in terms of clinical remission at W102 (both CD and UC) or endoscopic response at W102 (CD) after DE. Also, patients showed improvement in other efficacy endpoints after DE (Table 1). Compared to the first DE visit, patients who escalated the dose had a statistically significant reduction of more than half in mean modified Mayo score in UC (5.9 vs 2.1, P<0.0001) and mean CDAI score in CD (270.58 vs 76.31, P<0.0001) at W102.
The incidence rate of treatment-emergent adverse events (TEAEs) in the maintenance and extension phase of both studies was comparable between patients with and without DE (In UC, 84.7% [61/72] vs 78.1% [132/169], In CD, 86.8% [33/38] vs 79.7% [118/148]). Among these, TEAEs of infection were as follows; In UC, 40.3% (29/72) vs 43.2% (73/169), In CD, 55.3% (21/38) vs 42.6% (63/148). The incidence rate of treatment-emergent serious adverse events in the maintenance and extension phase of both studies was also comparable between patients with and without DE (In UC, 12.5% [9/72] vs 10.1% [17/169], In CD, 13.2% [5/38] vs 10.8% [16/148]).

Table 1. Summary of efficacy outcome in CT-P13 SC treated patients at Week 102
CT-P13 SC in LIBERTY-CD			CT-P13 SC in LIBERTY-UC
	Proportion of patients achieving efficacy outcomes at W102 regardless of dose escalation, n/N* (%)	Proportion of patients with dose escalation achieving efficacy outcomes at W102, n’/N** (%)		Proportion of patients achieving efficacy outcomes at W102 regardless of dose escalation, n/N (%)	Proportion of patients with dose escalation achieving efficacy outcomes at W102, n’/N’ (%)
Clinical remission¹	142/180 (78.9%)	26/37 (70.3%)	Clinical remission⁷	132/237 (55.7%)	25/71 (35.2%)
Endoscopic response²	102/180 (56.7%)	15/37 (40.5%)	Endoscopic-histologic mucosal improvement⁸	119/237 (50.2%)	21/71 (29.6%)
Clinical response³	148/180 (82.2%)	25/37 (67.6%)	Clinical response⁹	167/237 (70.5%)	43/71 (60.6%)
Corticosteroid-free remission⁴	44/74 (59.5%)	13/19 (68.4%)	Corticosteroid-free remission¹⁰	49/96 (51.0%)	14/41 (34.1%)
Clinical remission (alternative definition)⁵	131/180 (72.8%)	24/37 (64.9%)	-	-	-
Endoscopic remission⁶	71/180 (39.4%)	8/37 (21.6%)	-	-	-
n = Number of patients achieving efficacy endpoints at Week 102 regardless of dose escalation; N= Number of patients who were randomly assigned to CT-P13 SC 120 mg arm and treated in extension phase and have a SES-CD score of at least 6 (or at least 4 if isolated ileal disease) at Screening; n’ = Number of patients achieving efficacy endpoints at Week 102 among dose-escalated patients; N*= Number of patients with dose escalation to CT-P13 SC 240 mg prior to Week 102 in CT-P13 SC 120 mg arm and treated in extension phase and have a SES-CD score of at least 6 (or at least 4 if isolated ileal disease) at Screening; N = Number of patients who were randomly assigned to CT-P13 SC 120 mg arm and treated in extension phase; N’= Number of patients with dose escalation to CT-P13 SC 240 mg prior to Week 102 in CT-P13 SC 120 mg arm and treated in extension phase. Clinical remission, defined as an absolute Crohn’s disease activity index (CDAI) score of <150 points Endoscopic response at Week 102, defined as > 50% decrease in Simplified endoscopic activity score for Crohn’s disease (SES-CD) score from the baseline value Clinical response, defined as a decrease in CDAI score of 100 points or more from the baseline value Corticosteroid-free remission, defined as being in clinical remission (by an absolute CDAI score of <150) in addition to not receiving any corticosteroids for at least 8 weeks prior to Week 102, among the patients who used oral corticosteroids at baseline Clinical remission, defined as an average worst daily abdominal pain (AP) score of ≤1 (using 4-point scale) and an average daily loose/watery stool frequency (SF) score of ≤3 (of Type 6 or Type 7 on BSFS) with no worsening in either average score compared with the baseline value. Endoscopic remission, defined as an absolute SES-CD score of ≤4 with no sub-score of >1 Clinical remission, defined as modified Mayo score with stool frequency subscore of 0 or 1 point, rectal bleeding subscore 0 point, and endoscopic subscore 0 or 1 point Endoscopic-histologic mucosal improvement, defined as absolute endoscopic subscore of 0 or 1 point from modified Mayo score and an absolute Robarts Histopathology Index (RHI) score of 3 points or less with an accompanying lamina propria neutrophils and neutrophils in epithelium subscore of 0 point Clinical response, defined as decrease in modified Mayo score from baseline of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point Corticosteroid-free remission, defined as being in clinical remission (by modified Mayo score) in addition to not requiring any treatment with corticosteroid for at least 8 weeks at Week 102, among the patients who used oral corticosteroids at baseline

Conclusion

DE of CT-P13 SC from 120 mg to 240 mg Q2W following IV induction in patients who initially respond but subsequently lose response, shows clinical efficacy over an extended observation period of 102 weeks. Safety profiles were generally comparable between patients with or without DE, and no new safety concerns were found after DE as well in long term treatment.

References

1 Taxonera C et al. Infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis. Digestive Diseases and Sciences 2015; 60 (10): 3075-3084
2 Cesarini M et al. Dose optimization is effective in ulcerative colitis patients losing response to infliximab: A collaborative multicentre retrospective study. Dig Liver Dis.2014; 46(2): 135-139
3 S. Danese et al. MP362 Subcutaneous infliximab (CT-P13 SC) dose escalation as an option for managing the loss of response in inflammatory bowel disease: post hoc analysis of LIBERTY-UC study and LIBERTY-CD study. Gastroenterology. Volume 166, Issue 3, Supplement, 2024, Page S13

Disclosure

• S. Schreiber: Consultancy and personal fees from AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Gilead, HIKMA, IMAB, Janssen, MSD, Morphic, Pfizer, Protagonist, Provention Bio, Sandoz, Takeda, and Theravance.
• J.F. Colombel: Receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; Receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, Vifor; Hold stock options in Intestinal Biotech Development.
• S.B. Hanauer: Consultancy from AbbVie, Allergan, Amgen, Arena, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cosmos, Catalys Pacific, Covance, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Progenity, Prometheus, Receptos, Salix, Samsung Bioepis, Seres Therapeutics, Sorriso, Takeda, TLL, UCB, Vhsquared; Clinical Research for AbbVie, Allergan, Amgen, Celgene, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer, Prometheus, Receptos, Takeda, UCB; Speaker for AbbVie, Bristol Myers Squibb, Janssen, Pfizer, Takeda; Independent Data Monitoring Conference for Arena, Boehringer Ingelheim, Bristol Myers Squibb, Gossamer, Prometheus, Protagonist.
• W. Sandborn: Consulting fees from Alimentiv, Shoreline Biosciences; Stock or stock options from Prometheus Biosciences, Prometheus Laboratories, Ventyx Biosciences, Mirador Therapeutics; Employee at Ventyx Biosciences, Mirador Therapeutics; Board of Directors at Prometheus Laboratories.
• B.E. Sands: Consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio.
• S. Danese: Consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor. Reports lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda.
• S.J. Lee, S.H. Kim, Y.J. Bae, S.H. Lee, S.G. Lee, J.H. Lee, J.M. Kim, G.H. Park, J.M. Lee, J.H. Lee are Employee of Celltrion, Inc.

Event

UEG Week Vienna 2024

Topics

IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

Optimising biological treatment in IBD

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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