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

Although Endoscopic Retrograde Cholangiopancreatography (ERCP) has played an important role in the diagnosis and treatment of biliary and pancreatic diseases since its inception, the gallbladder is still considered a “blind spot” or inaccessible area for ERCP.

Aims & Methods

This study was intended to evaluate the technical success rate, safety, and clinical application value of per-oral cholangioscopy-guided transpapillary cystic duct approach for Gb-NOEES, and to explore the feasibility of Natural Orifice Endoluminal Endoscopic Surgery (NOEES) in the diagnosis and treatment of gallbladder diseases.
Patients with gallbladder diseases who received Gb-NOEES treatment from January 2023 to November 2024 were retrospectively included in a single-center study. Inclusion criteria: Patients are preoperatively diagnosed with gallstones, gallstones combined with common bile duct stones, gallstones combined with intrahepatic stones, acute cholecystitis, and gallbladder polyps. Exclusion criteria: patients with asymptomatic gallstones, patients with gallbladder cancer, and patients at risk of gallbladder cancer. All procedures were performed by experts with ≥10 years of experience in digestive endoscopy, and postoperative follow-up period ranged from 2 to 26 months.

Results

A total of 100 patients were included (58 males and 42 females, with an average age of 47±15.1). The disease distribution is shown in Table 1. The technical success rate of Gb-NOEES was 99% (99/100), and the average operative time was 130±59 minutes. The complication rate was 4%: 3 cases of gallbladder perforation (1 case of successful conservative treatment, and 2 cases of conversion to laparoscopic surgery), and 1 case of postoperative bleeding (successful conservative treatment). No severe pancreatitis or death occurred. Treatment outcomes: Gallstone clearance rate was 98% (78/80), with the largest stone measuring 4.0 cm, and up to 52 stones removed in a single operation. Complete excision rate of gallbladder polyps was achieved in 100% (15/15), with long diameter of polyps ranging from 4 mm to 15 mm, and up to 8 polyps excised in a single operation. Drainage success rate for acute cholecystitis was 100% (4/4). One case of early-stage gallbladder cancer was incidentally detected. During the follow-up period, the recurrence rate of stones was 2.5% (2/80), and there was no recurrence of polyps.

Conclusion

Gb-NOEES demonstrated favorable safety profile (complication rate was 4%) and high efficacy (overall success rate was 98%) in the diagnosis and treatment of gallbladder diseases. This technique has advantages of both lesion removal and organ preservation, offering a new minimally-invasive treatment option for gallbladder diseases. However, its clinical application value requires further validation through multi-center studies.

Table 1. Disease Distribution of Patients

Disclosure

There is no conflict of interest.