Introduction

Non-celiac gluten/wheat sensitivity (NCGWS) is characterized by gastrointestinal and extra-intestinal symptoms triggered by gluten/wheat ingestion. Symptoms of NCGWS overlap with those of irritable bowel syndrome (IBS) or functional dyspepsia (FD). Due to diagnostic challenges and symptom overlap, data on the prevalence and predictors of NCGWS among patients with IBS or FD, especially those with refractory symptoms, are limited.

Aims & Methods

This was a prospective, multicentric, double-blind, placebo-controlled, crossover trial conducted from October 2021 to March 2023 in India.This was prospectivly registered with the clinical trials Registry, INDIA (CTRI/2021/10/037323). Adults aged 18–65 years with Rome IV-defined irritable bowel syndrome (IBS) or functional dyspepsia (FD) refractory to standard treatment were enrolled after excluding celiac disease, wheat allergy, and alarm features. Participants underwent a two-step diagnostic protocol. In Step I, patients adhered to a 6-week strict gluten-free diet (GFD) under dietitian supervision. Weekly assessments of gastrointestinal and extra-intestinal symptoms, health-related quality of life (HRQoL), and psychological scores were performed using validated instruments. Gluten responders—defined by ≥30% reduction in one to three primary symptoms—were advanced to Step II: a randomized, double-blind, placebo-controlled gluten challenge with crossover. Subjects received indistinguishable gluten or placebo cookies (8 g/day) for one week, followed by a one-week washout and crossover. A ≥30% symptom difference between gluten and placebo phases confirmed non-celiac gluten/wheat sensitivity (NCGWS). Primary outcome was NCGWS prevalence; secondary outcomes included symptom and HRQoL changes post-GFD and predictors of NCGWS. Statistical analyses included intention-to-treat principles and multivariable regression to identify baseline predictors.

Results

Of the 252 patients screened, 177 were enrolled for 6-week GFD (step I), and 154 patients completed this phase (mean age 41.9±14.2 years, 53.2% males). Eighty two (52.3%) patients responded to GFD, of whom 77 entered step 2 (DBPCGC). Thirty one (20.1%) patients had significant symptom worsening on blinded gluten ingestion, suggesting the presence of NCGWS. Independent predictors of NCGWS were female gender, FD-IBS overlap, headache, fatigue, and anxiety. Significant improvements in gastrointestinal symptoms, health-related quality of life, and psychological scores were observed after GFD in responders. No significant impact of diet sequence was noted.

Conclusion

Introduction

Chronic intestinal pseudo-obstruction (CIPO) is a rare disease where impaired propulsive activity of the gut leads to bowel dilatation without an anatomical obstruction. There is no single assessment that comprehensively assesses the severity of symptoms and their impact on patients. Our aim was to develop a CIPO-specific electronic patient-reported outcome (ePRO), the CIPO Daily Diary^© (CIPO eDD), for clinical trials.

Aims & Methods

The CIPO eDD was developed per FDA guidelines^1,2 in a noninterventional, cross-sectional, qualitative interview study. This multi-stage process started with a targeted literature review and GAP analysis, with subsequent input from experts and patients. Literature reviews identified key signs and symptoms, and outcomes previously used in CIPO. Interviews with 3 clinicians experienced in diagnosing and treating CIPO, and insights from a steering committee that included the 3 clinicians and 2 external consultants, identified draft elements for the CIPO eDD. The draft CIPO eDD underwent iterative (4 rounds) hybrid concept elicitation (CE)/cognitive interviews and usability testing (CIUT) with patients from the USA (aged 18–80 years) with physician-confirmed CIPO diagnosis. For CE, patients answered open-ended questions about their CIPO experiences. CIPO signs, symptoms and impacts (concepts) emerged spontaneously from the responses. For CIUT, patients completed the CIPO eDD and reviewed the comprehensiveness, relevance and clarity of items. Textual analysis of interview transcripts guided amendments to the CIPO eDD items based on patient feedback. Following the initial CE/CIUT interviews, the same patients answered follow-up questions about the draft CIPO eDD to refine the items and to obtain qualitative and preliminary quantitative evidence for the potential revision or removal of items.

Results

Overall, 14 patients (female, n=10; mean [SD] age and time since diagnosis, 55.3 [15.5] and 4.3 [4.0] years, respectively) were interviewed. Concept saturation was reached after 3 rounds of CE/CIUT, with 15 of the 25 unique CIPO signs and symptoms included in the CIPO eDD (Table). Based on feedback from follow-up interviews (12 patients), no changes were made to items in the draft CIPO eDD. Minor changes were made to four items (vomiting, regurgitation, early satiety and CIPO episodes) suggested by qualitative data and the steering committee to improve clarity; the order of the nausea and vomiting items was switched. The sorting exercise did not identify any items for addition/removal or revision based on the qualitative evidence, with most patients indicating that all items should remain in the diary.

Conclusion

We have developed a de novo CIPO-specific ePRO per established FDA guidelines.^1,2 A final scoring system of the CIPO eDD based on the 15 items is in development. Ongoing quantitative assessment and psychometric validation of the CIPO eDD will enable its use in monitoring CIPO severity in clinical trials, thus supporting the development of effective therapies.

Table. Final items for the CIPO Daily Diary, and amendments from patient interviews

References

1. FDA. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-reported-outcome-measures-use-medical-product-development-support-labeling-claims (Accessed April 15, 2025).
2. FDA. Patient-Focused Drug Development: Collecting Comprehensive and Representative Input. 2009. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/patient-focused-drug-development-collecting-comprehensive-and-representative-input (Accessed April 15, 2025).

Disclosure

MG has received research support from Alexza Pharmaceuticals, Alfasigma, Donga and Takeda; and is an advisory board member for Alfasigma, Ardelyx and Evoke Pharma.
ViS is an advisory board member and/or speaker for Alfasigma, Bayer, Bromatech, Falck and GE Healthcare; and receives research support from Alfasigma.
JT has given scientific advice to Aclipse, Adare Pharma Solutions, Alfasigma, Clasado, Danone, Dr Falk Pharma, FitForMe, Ironwood, Kyowa Kirin, Menarini, PRO.MED.CS, Recordati, Takeda, Truvion Healthcare, Tsumura and Zealand Pharmaceuticals; receives research support from BIOHIT Healthcare, Kyowa Kirin, ProMed, Sofar and Takeda; and is a speaker for Abbott, Biocodex, Mayoly, Menarini, ProMed, Reckitt Benckiser, Schwabe, Takeda, Thai Meiji Pharmaceutical and Truvion Healthcare.
SM, EP and VaS are employees of Alfasigma S.p.A.
This study was sponsored by Alfasigma S.p.A.
The authors would like to thank all of the Alfasigma team who were involved in this study for their contributions to study conceptualization, study design, methodology, data curation, formal analysis, data interpretation and endorsement of the study design. In addition, the authors would like to thank the external consultants for their time and expertise, and the principal investigators at the collaborating sites for patient recruitment and data collection.
Medical writing support for the development of this abstract was provided by Hannah Stephens, PhD, of PharmaGenesis London, London, UK, and was funded by Alfasigma S.p.A.

Introduction

Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are common disorders of gut-brain interaction (DGBI), and bloating and visible abdominal distension are common symptoms among individuals with IBS and/or FD. Bloating refers to a subjective sensation of tension or pressure in the abdomen, which may or may not be reported together with visible abdominal distension. The underlying pathophysiological mechanisms may differ, with bloating suggested to be more related to hypersensitivity and visible abdominal distension to altered motility. The prevalence of these two symptoms in IBS and FD, especially as distinct symptoms, is not well known.

Aims & Methods

The aim was to investigate the link between bloating and distension with IBS and FD. Therefore, we performed a population-based internet survey of adults in the US, UK, and Mexico, including Rome IV IBS and FD diagnostic questions, somatization (PHQ-12), and psychological distress (PHQ-4). Four groups were created: those meeting the Rome IV criteria for IBS only, FD only, both IBS+FD, and a reference group including individuals without IBS, FD and organic diagnoses that could result in IBS- or FD-like symptoms. Within each group, we identified individuals who reported ≥weekly bloating alone (B), ≥weekly visible abdominal distension alone (D), ≥weekly combined B+D, or neither of both. The relationship between B, D and B+D in those with IBS and/or FD vs. the reference group was investigated using logistic regression models.

Results

The analysis included 5,448 participants (49.7% female; mean age 46.5 years, range 18-99), with 131 meeting criteria for IBS only, 360 for FD only, 217 for IBS+FD and 4,740 for the reference group. A larger proportion of individuals with IBS only (64.9%), FD only (50.6%), and especially those with IBS+FD (88.5%) reported bloating and/or visible abdominal distension compared to the reference group (13.7%). In the IBS only group, 16.0% reported bloating alone, 8.4% visible abdominal distension alone, and 40.5% combined bloating and visible abdominal distension. In the FD only group this was 12.8% (B), 8.9% (D), and 28.9% (B+D), and in the IBS+FD group 18.9% (B), 8.3% (D), and 61.3% (B+D), respectively. Reporting bloating alone or combined bloating and visible abdominal distension was strongly linked to fulfilling criteria for IBS only, FD only, and concomitant IBS+FD vs. the reference group, with weaker links for visible abdominal distension in the absence of bloating (Table). After adjusting for age, sex, BMI, psychological distress and somatization, the links persisted. The strongest association was observed between combined bloating and visible abdominal distension (vs. neither) and concomitant IBS+FD (vs. the reference group); adjusted odds ratio 28.6 [95%CI 17.6-46.6].

Conclusion

Bloating and visible abdominal distension as distinct and overlapping symptoms are strongly linked to IBS, FD, and concomitant IBS+FD in the general population. Assessing bloating and visible abdominal distension as separate symptoms may be important to enable individualized treatment for individuals with IBS and FD.