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

Obesity is a global health challenge associated with significant morbidity, mortality, and economic burden. Endoscopic Sleeve Gastroplasty (ESG) has emerged as a safe, incisionless, and minimally invasive alternative to bariatric surgery for patients with obesity who are either unwilling or unsuitable for surgical options. While ESG has demonstrated promising short-term results in terms of weight loss and metabolic improvement, there remains a paucity of data on long-term outcomes, particularly beyond one year. This study aims to evaluate the long-term efficacy of ESG in a large Asian cohort, focusing on total body weight loss (TBWL) as the primary outcome, with body mass index (BMI) change and absolute weight loss as secondary outcomes.

Aims & Methods

We conducted a retrospective review of 236 patients who underwent ESG at Singapore General Hospital between November 2020 and December 2025. All procedures were performed by a single experienced endoscopist using a U-shaped suturing pattern. The primary outcome was the percentage of total body weight loss (%TBWL) at 6, 12, and 24 months post-procedure.

Results

The cohort consisted predominantly of female patients (69%), with the majority being of Chinese ethnicity (42.8%). The mean age at baseline was 41.4 years (SD ± 10.6), and the mean baseline BMI was 35.0 kg/m² (SD ± 6.1). All ESG procedures were technically successful, with an average of five sutures placed per patient and a mean procedure time of 75 minutes (SD ± 17). No major complications were reported, and the average hospital stay was one day.
Follow-up data were available for 114 patients at 6 months, 86 at 12 months, and 41 at 24 months. The mean percentage total body weight loss was 15.9% (SD ± 10.5) at 6 months, 12.7% (SD ± 7.8) at 12 months, and 9.9% (SD ± 7.8) at 24 months, reflecting a sustained reduction in weight over time. As secondary outcomes, BMI decreased significantly from baseline by a mean of 6.0 kg/m² (SD ± 5.3) at 6 months, 4.2 kg/m² (SD ± 5.7) at 12 months, and 3.5 kg/m² (SD ± 5.7) at 24 months (all p < 0.001). These were accompanied by corresponding mean weight losses of 16.8 kg (SD ± 17.1), 12.1 kg (SD ± 8.6), and 9.6 kg (SD ± 9.0) at the respective timepoints, all statistically significant (p < 0.001).

Conclusion

ESG is a safe and effective endoscopic intervention for weight loss, with sustained and clinically meaningful reductions in total body weight, BMI, and absolute weight observed up to two years post-procedure. These real-world data from a large tertiary Asian centre support the long-term utility of ESG as a viable non-surgical option for obesity management.

Disclosure

​Nil

Introduction

The eosinophilic esophagitis (EoE) endoscopic reference score (EREFS) is the validated scoring system for endoscopic findings of EoE. EREFS findings are currently scored cumulatively and correlate modestly with histological disease activity (HDA), symptoms, and adaptive behaviors. However, inflammatory and fibrotic findings may reflect different aspects of EoE, but this has never been evaluated.

Aims & Methods

We investigated the correlation of EREFS inflammatory and fibrotic subscores with HDA, symptoms and adaptive behaviors. In three tertiary referral centres for EoE, consecutive adults (>18 years) undergoing upper endoscopy for suspected or follow up EoE were prospectively enrolled. EREFS was scored as follows: edema 0-1; rings 0-3; exudates 0-2; furrows 0-2; stricture 0-1. The EREFS inflammatory sub-score (EREFS-i) combined the scores of edema, exudates and furrows. The EREFS fibrotic sub-score (EREFS-f) combined the scores of moderate-severe rings (score ≥2) and stricture. Subsequently, at least six esophageal biopsies were collected to assess HDA based on peak eosinophil count/high-power field (PEC/HPF) (active EoE PEC ≥15/HPF; EoE in remission: PEC<15/HPF). Symptoms were assessed using the dysphagia symptoms questionnaire (DSQ). Adaptive behaviors were assessed using the Pisa EoE Adaptation Questionnaire v1.0 (PiEAQ) [reference 1]. Clinical characteristics were recorded. Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons. ROC curve analysis was used to calculate the diagnostic accuracy (AUC). Spearman’s test and linear regression models were used to assess relationships between variables. Significance threshold was p<0.05.

Results

121 patients were included. 58% had active EoE, 42% were in histological remission. Baseline clinical data are reported in Table 1. The EREFS total score had modest AUC for predicting HDA (0.68) and did not show significant correlation with DSQ and PiEAQ. In contrast, EREFS-i had AUC of 0.73, with 88.2% sensitivity and 51.4% specificity for predicting HDA, being significantly more accurate compared to the EREFS-f (p<0.001; Figure 1). There was a significant correlation between EREFS-i and PEC/HPF with Spearman’s Rho=0.5 (p<0.001), with linear regression showing that an increase of 1 point of any inflammatory feature corresponded to an increase of 12 eosinophils/HPF (p<0.0001). In contrast, EREFS-f correlated significantly with the use of adaptive behaviors assessed with PiEAQ [Spearman’s Rho of 0.6 (p<0.001); Figure 2], with linear regression showing that an increase of 1 point of any fibrotic feature corresponded to an increase of one adaptive behavior (p=0.001). EREFS, EREFS-i, and EREFS-f had nonsignificant negative correlation with DSQ (p>0.05 for all).

Conclusion

We confirmed that, while total EREFS provides a global assessment of endoscopic disease severity, it lacks correlation with histological and clinical disease activity. However, we demonstrated that EREFS-i correlates significantly with PEC and predicts PEC/HPF and that EREFS-f correlates significantly with the use of adaptive behaviors assessed with PiEAQ, which represent known clinical markers of disease activity. Neither EREFS-i nor EREFS-f correlated significantly with DSQ. In conclusion, we showed that, compared to the total EREFS, EREFS sub-scores improve the correlation between endoscopy findings with histology and clinical disease activity markers. Applied to clinical practice, our results represent another step towards precision medicine in the setting of EoE.

References

[reference 1] Visaggi P, Del Corso G, Solinas I, Ovidi F, Adamo G, Dulmin I, Baiano Svizzero F, Bellini M, Savarino EV, de Bortoli N. Adaptive Behaviors, Esophageal Anxiety, and Hypervigilance Modify the Association Between Dysphagia Perception and Histological Disease Activity in Eosinophilic Esophagitis. Am J Gastroenterol. 2024 Dec 30. doi: 10.14309/ajg.0000000000003272. Epub ahead of print. PMID: 39787341.

Disclosure

Speaker or consultancy for Apogee Therapeutics, Dr Falk Pharma, Malesci, JB Pharmaceuticals, Sanofi

Introduction

Acute cholecystitis (AC) is a relatively frequent complication of ERCP with placement of self-expandable metal stents (SEMS) for distal malignant biliary obstruction (DMBO). SEMS design seems irrelevant, whereas neoplastic Cystic duct infiltration (CDI) has been claimed to be the most important independent predictor. However, data regarding incidence and risk factors are scant.

Aims & Methods

The primary aim of this study was to evaluate the incidence and risk factors of AC following ERCP with SEMS placement in patients with DMBO clustered according to the presence or absence of CDI evaluated by EUS.
This is a single tertiary center prospective study conducted between Feb-2024 and Jan-2025. All consecutive patients candidate to EUS and ERCP for characterization and endoscopic treatment of DMBO treated with a partially covered SEMS were included in the study (ClinicalTrials.gov identifier NCT04813055).
Two independent endosonographers blindly assessed the presence of CDI and other morphological risk factors (such as cholelithiasis or cholecystitis) at EUS.
Two independent endoscopists estimated CD coverage by the SEMS and other risk factors (such as gallbladder cannulation and contrast opacification) at ERCP.
Clinical outcomes were evaluated by one independent assessor during admission, at 30 days and then every 60 days.
The primary outcome was the onset of AC among patients with and without CDI. Risk factors for AC were evaluated through multivariate logistic regression model.

Results

A total of 109 patients with DMBO were included (median age 71 [IQR 62-77], female 38.5%, pancreatic adenocarcinoma 87.2%).
At EUS, prevalence of CDI was 16.5%; gallstones and sludge were present in 6.4% and 73.4% of cases.
At ERCP, where a 6-cm and 4-cm SEMS were used in 64.2% and 34% of cases, the CD was covered by the SEMS in 40.7% of the procedures.
Median follow-up was 94 [35-175] days.
Seven (6.4%) patients experienced post-ERCP pancreatitis whereas 8 (7.3%) experienced post-ERCP AC, after a median time of 6.5 [5-31] days post-procedure. AC required additional intervention in 57.1% of cases.
The rate of post-ERCP AC did not differ between patient with and without CDI, being 11.1% versus 6.6%, p=0.503.
Amongst patients with AC, ASA scores were lower while placed SEMS were longer, and the rate of CD coverage was significantly higher (87.5% versus 37%, p=0.005); the rate of CDI was higher but the difference was not significant.
At multivariate analysis, CD coverage by the SEMS was the only independent predictor of post-ERCP AC (OR[95% CI] = 13.8 [1.5-123.6].

Conclusion

In the context of SEMS placement for DMBO, post-ERCP AC is relatively more frequent than post-ERCP pancreatitis. EUS ahead of ERCP can help in predicting morphological risk factors for this event.
Coverage of the cystic duct by the SEMS appears to be the most important predictor, independent of cystic duct infiltration, potentially proposing a new high-risk group for this event, to be validated in future studies.

Introduction

In the southwest Netherlands, hospitals collaborate to provide high quality, uniform care for inflammatory bowel disease (IBD). To achieve this, a care pathway (CP) was implemented for treating IBD with biologics and small molecules (1). The CP consists of protocols addressing different stages in IBD treatment, such as initiation and switching of therapy, frequency and type of follow-up. This study assessed the adherence to the CP and identified barriers and facilitators to its implementation.

Aims & Methods

A mixed-methods study was conducted. Quantitative data was used to evaluate the adherence to different protocols of the CP and was collected retrospectively from electronic health records (EHRs) from December 2020 until March 2023. Surveys and semi-structured interviews were used to identify barriers and facilitators, using the Extended Normalisation Theory. Surveys were sent to all healthcare providers and interviews were conducted with gastroenterologists, IBD-nurses, healthcare assistants, and IT-personnel.

Results

A total of 299 patients were included. Adherence to the CP regarding the documentation of travel plans and vaccination status improved after implementing the CP (15% pre-implementation vs. 33% post-implementation), as well as written communication with general practitioners (31% vs. 83%) and body weight registration (12% vs. 50%). Among patients switching medication, 25% had a repeated screening for HIV, tuberculosis, and hepatitis B and C documented if prior tests were over a year old. Post-implementation, scheduling outpatient visits were more closely aligned with CP recommendations across CP protocols (57% vs. 100%), as did blood test ordering (10% vs. 44%). Disease activity scoring with validated questionnaires remained low (7% vs. 21%).  Adherence to registering medication adherence, current smoking status, and side effects during annual outpatient visits remained low (18% vs. 40%).
Of 85 surveys, 42 were completed, and 11 interviews were conducted. Facilitators were improving collaboration between healthcare providers and the potential to standardise care. Barriers included the complexity of the use in EHRs, difficulty for healthcare providers to change their current routine, and the heterogeneity of IBD.

Conclusion

A CP for the treatment of IBD with biologics and small molecules has been implemented to improve IBD care, however, adherence appears to be challenging, partially contributed to the difficulty healthcare providers experience in changing their behaviour. The gradual improvement indicates that increased familiarity with the CP may enhance adoption. Discrepancies between performed and documented tasks in EHRs may also contribute to lower adherence rates, which could be improved by audit and feedback sessions.

References

1. van Linschoten R, van Leeuwen N, Nieboer D, Birnie E, Scherpenzeel M, Verweij KE, et al. Value-based care pathway for inflammatory bowel disease: a protocol for the multicentre longitudinal non-randomised parallel cluster IBD Value study with baseline period. (2044-6055 (Electronic))

Disclosure

Drs. Visser received speaker fees from Lilly outside the submitted work. Prof. Dr. van der Woude reports grants from Pfizer and Janssen and personal fees from AbbVie and Celltrion outside the submitted work. Dr. van Noord reports personal fees from Janssen, Takeda, and Falk outside the submitted work. Dr. West reports personal fees from AbbVie, Janssen, and Pfizer outside the submitted work.