Introduction

Patients with irritable bowel syndrome (IBS) frequently seek dietary advice. However, few evidence-based options exist. Societal guidelines recommend traditional dietary advice (TDA) as first-line therapy, with the cumbersome and resource-intensive low FODMAP diet reserved as second-line therapy.
Recent pilot data suggests that the Mediterranean diet (MD), renowned for its general health benefits, improves the symptoms of IBS. Whether it can be considered another first-line dietary option is not known.

Aims & Methods

This randomized non-inferiority clinical trial assigned 139 individuals with IBS, from across the United Kingdom, to follow the MD (n=68) or TDA (n=71) for six weeks. The primary endpoint was the proportion of participants achieving clinical response, defined as a ≥50-point reduction in the IBS Symptom Severity Scale (IBS-SSS). Secondary outcomes included changes in IBS-SSS, psychological health, somatic symptom reporting, quality of life, diet satisfaction, and the Mediterranean Diet Adherence Screener (MEDAS).

Results

Baseline characteristics (mean age 40.4 [range 19-65] years, 80% female) and IBS-SSS (mean 309, SD 90) were similar between groups. On modified intention-to-treat analysis, the primary endpoint was met by 62% (95% CI 50%-73%) taking a MD versus 42% (95% CI 31%-55%) taking TDA. The difference in clinical response between the groups was in favor of the MD (20%, 95% CI 4%-36%), demonstrating it to be non-inferior based on the a priori defined requirement for the CI to exclude -5%. Rather, the MD was superior to TDA (odds ratio 2.3 [95% CI: 1.16-4.64], p = 0.017). There was a greater reduction in the mean IBS-SSS following a MD than TDA (-101.2 vs. -64.5, ∆-36.7 [95% C.I. -70.5 to -2.8], p=0.034). No significant differences were observed between the groups with regards to changes in mood, somatic symptoms, quality of life or diet satisfaction. The MEDAS significantly increased following a MD compared with TDA (p< 0.001).

Conclusion

The MD is non-inferior (rather, it demonstrated superiority) to TDA in managing the symptoms of IBS, and can be considered as another first-line dietary option.
Clinical trials registration: NCT05985018

Disclosure

Nil

Introduction

Human transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis, spurring development of the oral TG2 inhibitor ZED1227. In the phase 2a CEC-003/CEL study in CeD patients on a gluten-free diet (GFD), once-daily treatment with ZED1227 with gluten challenge (3 g/day) for 6 weeks led to significant improvement in the ratio of intestinal villous height to crypt depth (VH:CrD) versus placebo.¹ Despite adherence to a gluten-free diet, up to half of CeD patients report persistent symptoms often combined with varying degrees of small intestinal injury. Hence, potential treatments for CeD should ideally address these symptoms and improve mucosal injury.

Aims & Methods

The aim of the present study was a dose-ranging trial of ZED1227 in CeD patients with residual symptoms and villous atrophy despite a GFD. This was a double-blind, randomized, placebo-controlled phase 2b study. It enrolled adult CeD patients who had followed a GFD for at least one year and who experienced at least one moderate or severe gastrointestinal (GI) symptom in the month prior to baseline. All patients underwent an initial 5-week placebo run-in phase, followed by endoscopy and 1:1:1:1 randomization of patients with VH:CrD ≤2.5. Treatment was placebo thrice-daily (TID) or ZED1227 at doses of 10 mg TID, 25 mg TID, or 50 mg once-daily (QD) for 12 weeks. No gluten challenge was carried out. The primary endpoint was the rate of patients with both improvement by ≥ 0.4 in VH:CrD and improvement by ≥ 15% in either of two symptom scores (non-stool GI or diarrhea severity) on the celiac disease symptom diary (CDSD) from the end of the run-in phase to week 12. Key secondary endpoints included the change in VH:CrD, change in CDSD GI total severity score, and safety.

Results

A total of 397 patients were randomized to the 4 arms, of whom 92.7% completed treatment. The primary endpoint was achieved by 27.1% of patients receiving 10 mg ZED1227 TID, 16.9% for 25 mg TID, 25.3% for 50 mg QD, and 19.3% for placebo, with no significant differences between any treatment arm and placebo. The mean change in VH:CrD ratio from baseline was 0.21 for 10 mg ZED1227 TID, 0.17 for 25 mg TID, and 0.26 for 50 mg QD versus 0.12 for placebo. Within-group changes from baseline to week 12 were statistically significant within each arm, while the between-group difference in changes was significant only for 50 mg ZED1227 QD versus placebo (p<0.05). Similarly, mean changes in the CDSD GI total severity score were -0.96 with 10 mg ZED1227 TID, -0.95 with 25 mg TID, -1.20 with 50 mg QD, and -1.05 with placebo. Improvements within each arm were again statistically significant, with no significant differences between any treatment arm and placebo. There were no notable differences in the rates of adverse events or serious adverse events (SAEs) between the study arms, and no SAEs related to the study drug were reported.

Conclusion

The CEC-004/CEL study did not meet its primary endpoint of combined improvement in histology and symptoms. However, changes in the VH:CrD ratio achieved with 50 mg ZED1227 QD were statistically superior to placebo, consistent with the results of the prior CEC-003/CEL study. Significant within-group improvement from baseline to week 12 in both histologic and symptom outcomes within the placebo group underscored the challenges of clinical trials without deliberate gluten exposure in patients with the heterogeneous symptom and histology typical of partially treated CeD. The favorable safety profile of ZED1227 was confirmed, and no new safety concerns were identified.

References

1. Schuppan D, Maki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, et al. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021;385(1):35-45.

Disclosure

Sponsor of the trial: Dr. Falk Pharma GmbH
Acknowledgement: This research was supported by Takeda.

Introduction

Up to 40% of patients with acute severe ulcerative colitis (ASUC) do not respond to infliximab (IFX)(1) presumably due to insufficient drug exposure (1, 2). We investigated whether personalised IFX induction using predefined serum concentrations was superior to standard dosing.

Aims & Methods

In this prospective, multi-centre trial, adult IFX-naive steroid-refractory ASUC patients were randomised 1:1 to standard (SD) or personalised IFX dosing (PD). After an initial 5 mg/kg IFX infusion, SD was 5 mg/kg IFX at week 2 and 6. In PD, additional 5 mg/kg IFX infusions were administered guided by a Bayesian pharmacokinetic algorithm (iDose™) aiming at IFX serum concentrations >28 ug/mL day 0-28 and >15 ug/mL day 29-42 (3). The primary composite endpoint was clinical and endoscopic response at day 42 (Lichtiger score <10 and ≥3 points drop and UCEIS ≥2 points drop from baseline). Video-endoscopies were performed at baseline, day 42 and 182 and scored by 2 expert readers (XR) with adjudication by a third XR and post hoc also by the DovaVision UC AI tool (AI-R)(4). Key secondary endpoints were day 42 clinical response, day 42 endoscopic response, day 182 clinical remission (Lichtiger ≤3), day 182 endoscopic remission (UCEIS ≤1 on all components), and safety.

Results

48 patients were randomised (23 PD/25 SD) and 31 completed the 26-week study (19 PD/12 SD). Patient characteristics were comparable. Median cumulative IFX dose until day 42 was 18.41 mg/kg [1.77, 20.27] for PD vs 13.79 mg/kg [10.38, 14.82] for SD. The primary composite endpoint at day 42 was not met with XR (57% in PD vs 44% in SD; p=0.564). However, AI-R showed a significantly higher composite response rate in PD (74% in PD vs 32% in SD; p=0.0047). PD showed higher day 42 clinical response vs SD (91% vs 64%; p=0.039). Day 42 endoscopic response was observed in 57% in PD vs 44% in SD (p=0.564) with XR and 74% in PD vs 32% in SD with AI-R (p=0.0047). The proportion of patients in clinical and endoscopic remission at day 182 was higher in PD than in SD (65% vs 36%; p=0.082). Day 182 endoscopic remission with AI-R was higher in PD (52% in PD and 20% in SD; p=0.0337). SAEs occurred in 9% of patients on PD vs 20% of patients on SD. Following an interim analysis, the trial was discontinued based on futility.

Table 1. Baseline characteristics

Conclusion

Personalised IFX dosing was superior to standard dosing in ASUC when endoscopies were read by AI. This is the first IBD study where the primary endpoint, missed by expert assessment, was overturned and met by AI assessment instead. This demonstrates the potential of AI to fundamentally improve clinical trial methodology.

References

1. Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49-54.
2. Papamichael K, Van Stappen T, Vande Casteele N, Gils A, Billiet T, Tops S, et al. Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14(4):543-9.
3. Ungar B, Mazor Y, Weisshof R, Yanai H, Ron Y, Goren I, et al. Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis. Aliment Pharmacol Ther. 2016;43(12):1293-9.
4. Byrne M, Requa J, Panaccione R, Panes J, Bressler B, East JE, et al. Development and Validation of a novel AI-based computer vision solution for Ulcerative Colitis severity scoring on video for real world using high-volume expert-annotated video frames. United European Gastroenterol J. 2025 Oct.

Disclosure

This project received grant support from Pfizer Inc. and research support from Baysient LLC, Buhlmann Laboratories and Dova Health Intelligence.