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AN INTERNATIONAL CONSENSUS ON THE DESIGN OF CLINICAL TRIALS FOR ADVANCED COMBINATION TREATMENT (ACT) IN INFLAMMATORY BOWEL DISEASE

Affiliations

1 IRCCS Ospedale San Raffaele, Universita Vita-Salute San Raffaele, Milan, Italy|||Western University, London, Canada

2 University Medical Centre Ljubljana, Ljubljana, Slovenia

3 University of Calgary, Calgary, Canada

4 University of Montreal Hospital Centre, Montreal, Canada

5 Cambridge University Hospital NHS Foundation Trust, Cambridge, United Kingdom

6 Department for Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Campus Benjamin Franklin, Berli

7 University of Lorraine, Inserm, NGERE, Nancy and Groupe Hospitalier prive Ambroise Pare-Hartmann, Paris IBD Centre, Neuilly-sur-Seine, France|||INFINY Institute, Department of Gastroenterology, CHRU Nancy, INSERM NGERE, Universite de Lorraine, Vandoeuvre-

8 Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven; Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium

9 Hospital Beatriz Ângelo, Loures, Portugal|||Hospital da Luz, Lisbon, Portugal

10 The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, United States|||Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, United States

11 Department of Gastroenterology, Amsterdam University Medical Centres, Amsterdam, Netherlands

12 Alimentiv Inc., London, Canada

13 IRCCS Ospedale San Raffaele, Universita Vita-Salute San Raffaele, Milan, Italy

14 Erlangen University Hospital, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany|||Deutsches Zentrum Immuntherapie, Erlangen, Germany

15 Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas Y Digestivas, Hospital Clínic de Barcelona, Barcelona, Spain

16 Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, United States

17 Western University, London, Canada|||Western University, London, Canada

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Abstract

Introduction

There is a lack of guidance regarding clinical trial design for advanced combination treatment (ACT) in patients with inflammatory bowel disease (IBD). Key uncertainties remain regarding aspects such as eligibility criteria, pharmacotherapy regimens, safety considerations, and standardised trial design configurations for both induction and maintenance phases.

Aims & Methods

We aimed to formulate expert recommendations regarding the design of ACT clinical trials in IBD. ACT was defined as the concomitant administration of 2 biological therapies, a biological plus an oral small molecule, or 2 small molecules.^1,2 A total of 17 gastroenterologists and precision medicine experts were invited to participate in a Modified RAND/University of California, Los Angeles Appropriateness Methodology (RAM) exercise, based on publication record, experience in clinical trial design, and/or expertise in personalised treatment strategies for IBD. The process began with development of a draft survey drawing from a previously published systematic review that identified 10 randomised controlled trials comparing ACT with advanced monotherapy for the treatment of immune-mediated diseases.² The survey covered 6 domains: (1) general considerations, (2) pharmacotherapies utilised in ACT regimens, (3) trial design configurations, (4) outcome timepoints, (5) outcome measures, and (6) precision medicine considerations. The RAM study evaluated 287 statements related to the design of ACT clinical trials in patients with IBD. The multidisciplinary panel of experts rated statement appropriateness on a 9-point Likert scale. Statements were subsequently categorised as appropriate, uncertain, or inappropriate based on the median panel rating and the presence of disagreement.

Results

ACT should consist of drugs with distinct mechanisms of action, avoiding combinations targeting the same biological pathway (Table 1). Panellists favoured combining therapies with distinct mechanisms of action and deemed the use of 2 drugs targeting the same pathway (eg, 2 anti-tumour necrosis factors) inappropriate. Combinations such as sphingosine-1-phosphate receptor modulators with α4β7 inhibitors were classified as appropriate, while the addition of thiopurines required case-specific consideration. Appropriate eligibility criteria included prior treatment failure and high risk for disease complications. Safety considerations were prioritised, with short-term use of high-risk regimens acceptable for induction therapy. Trial designs should compare ACT to monotherapy and allow for longitudinal evaluation. Co-primary endpoints of clinical remission and endoscopic response were endorsed, with safety outcomes including adverse events and infections. Precision medicine approaches, guided by biomarker analysis, were considered essential for further defining mechanistic pathways and monitoring treatment response.

Table 1. Summary of key recommendations
Category	Finding
Eligibility criteria	- It is appropriate to include participants at high-risk for disease-related complications. - It is appropriate to include participants who have failed conventional therapy. - Eligibility criteria should be based on a risk-benefit analysis of safety and efficacy data.
Pharmacotherapies	- The Advanced Combination Treatment (ACT) regimen should include drugs with distinct mechanisms of action. - Drug selection should not be based on route of administration and should be based on safety, clinical, endoscopic, biomarker, and pathway change data.
Trial design configurations	- The efficacy and safety of the ACT regimen should be compared to each monotherapy. - It is acceptable to assess ACT: as induction therapy, including as an add-on strategy; as maintenance therapy, including as a step-down, step-sequential, or on-demand strategy; using a treat-through, open-label induction followed by a randomised withdrawal, or re-randomised maintenance design.
Outcome timepoints	CD - Primary (induction): Week 8, 10, 12, or 14; primary (maintenance): Week 48 or 52. UC - Primary (induction): Week 6, 8, 10, 12, or 14; primary (maintenance): Week 48 or 52.
Outcome measures	CD - Efficacy: clinical remission + endoscopic response (co-primary). UC - Efficacy: clinical remission + endoscopic remission (composite). Both CD and UC - Safety: adverse events (AEs), serious AEs, withdrawal due to AEs, infections, serious infections, surgery, hospitalisation, AEs of special interest (AESIs).
Precision medicine	Collection every 2 or 4 weeks (induction)/4 or 8 weeks (maintenance): whole blood for immune cell population and differential gene expression analyses; serum for analyte immunoassay, metabolite, pharmacokinetics, and efficacy/safety-exposure analyses. Collection every 4 weeks (induction)/4 or 8 weeks (maintenance): plasma for exploratory biomarker analyses. Collection every 4 weeks (induction)/8 weeks (maintenance): stool for microbiome, protein, and metabolite analyses. Collection at all endoscopic procedures: mucosal biopsies for differential gene expression, advanced transcriptomic, and analyte immunoassay analyses.

Conclusion

Implementing standardised design elements for eligibility criteria, pharmacotherapy regimens, safety considerations, and trial design configurations will facilitate the conduct of efficient clinical trials of ACT.

References

1. Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022;71(12):2380-2387. Doi: 10.1136/gutjnl-2022-327025
2. Solitano V, Yuan Y, Singh S, Ma C, Nardone OM, Fiorino G, et al. Efficacy and safety of Advanced Combination Treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials. J Autoimmun. 2024;149:103331. Doi: 10.1016/j.jaut.2024.103331

Disclosure

Jurij Hanžel has received consultancy fees from Alimentiv Inc
Christopher Ma has received consulting fees and speaker’s fees from Alimentiv Inc.
Laurent Peyrin-Biroulet has received consulting fees from Alimentiv Inc.
Bram Verstockt has received consultancy fees from Alimentiv Inc.
Geert D'Haens reports consulting fees from Alimentiv Inc
Malcolm Hogan and Claire E. Parker are employees of Alimentiv Inc.
Federica Ungaro has nothing to declare.
Julian Panés has received consultancy fees/honorarium from Alimentiv Inc., and has served on data safety monitoring boards for Alimentiv Inc.
Remo Panaccione has received consultant fees and advisory board fees from Alimentiv Inc. (formerly Robarts).
Bruce E. Sands reports consulting fees from Alimentiv Inc.
Brian G. Feagan is the Senior Scientific Director at Alimentiv Inc.
Silvio Danese has received consultancy fees from Alimentiv Inc.
Vipul Jairath has received consultancy/advisory board fees from Alimentiv Inc.
Virginia Solitano, Robert Battat, Tim Raine, Britta Siegmund, Joana Torres, Saurabh Mehandru, and Raja Atreya report no conflicts of interest with Alimentiv Inc.

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

Optimising ulcerative colitis therapy (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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