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.

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.

Introduction

Crohn's disease (CD) is a chronic inflammatory condition of the digestive tract characterized by a cyclical course, the most frequent and feared complication is the formation of stenoses. The management of these stenoses is often multidisciplinary medico-surgical as well as endoscopic.
Endoscopy plays an essential role in the diagnosis, monitoring, and treatment of these stenoses, particularly through endoscopic dilations. The objective of our work is to study the role of endoscopic dilations during stenosing Crohn's disease in addition to medical treatment.

Aims & Methods

This is a single-center descriptive retrospective study carried out within our department over a period of 6 years: from January 2018 to January 2024, including all patients followed for stenosing Crohn's disease who underwent endoscopic dilation. We collected data related to age, history, location, phenotype, clinical symptoms, endoscopic data as well as evolution.

Results

We included 19 patients followed in our training for stenosing Crohn's disease who benefited from endoscopic dilation out of a total of 109 patients followed for Crohn's disease with a stenosing phenotype (17.4%). The average age was 45 years with extremes ranging from 20 to 71, with a male predominance and a M/F sex ratio: 2.8 (14 M and 5 F).
Three patients were smokers (15.8%), 6 patients underwent anterior ileocecal resection (31.6%) and a total colectomy ATCD in one patient (5.3%). The median time from diagnosis of Crohn's disease to formation of symptomatic stenosis was 9.3 years.
Clinically, abdominal pain was present in 8 patients (42.1%), Koenig syndrome in 7 patients (36.8%), diarrhea in 3 patients (21%), 4 patients (28.5%). had defecatory pain, evacuation constipation in 3 patients (15.8%) and late postprandial vomiting was present in 1 patient (5.3%).
The stenosis was at the last ileal loop in 5 cases (26.3%), 4 (21%) at the rectal level, 1 stenosis respectively at the colonic, anal, esophageal, pyloric and duodenal level (5.3% each) and 5 stenoses at the level of the anastomosis including 4 (21%) at the level of the ileocolic anastomosis and 1 at the level of the ileorectal anastomosis (5.3%).
The average length of the stenoses was 19.2 mm with extremes ranging from 5 to 40 mm. Dilations were carried out using hydrostatic dilation balloons whose caliber varied between 10 and 16.5 mm, 3 (15.8%) patients benefited from dilation to 16.5 mm, 7 (36.8%) at 12mm, 6 (31.6%) at 15mm, and 2 (10.5%) at 11mm.
11 patients benefited (57.9%) from a single dilation session, 7 patients benefited from 2 dilations (36.8%) and 1 patient (5.3%) had recourse to 5 dilations.
Primary success defined by the passage of the endoscope was possible in 15 patients (78.9%). Only one perforation type complication was noted, treated surgically.
The secondary success rate defined by the disappearance of symptoms was in 9 patients (47%). The average follow-up was 31.8 months and the clinical recurrence rate was 37.5% at 6 months. 4 patients (21%) benefited from additional surgery.

Conclusion

Endoscopic dilation is a minimally invasive treatment which constitutes an effective alternative to surgery in the management of stenoses during Crohn's disease; in our study more than half of our patients only had recourse to a single dilation session with a primary success of more than 78.9%, and a disappearance of symptoms at 6 months in almost half of the patients, thus making the use of surgery less frequent.