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), the most prevalent gastrointestinal disorder globally, has a significant impact on the quality of life of 10 - 15% of the population, with a higher prevalence among women than men. Despite the identification of certain contributing factors, the pathophysiology of IBS remains largely unknown.

Aims & Methods

We firstly performed Genome-wide association study (GWAS) on the IBS cohort from the All of Us Research Program and adjusted for sex, age, and top 10 principal components. We conducted GWAS meta-analyses of IBS and its subtypes in 80,737 IBS cases and 1,019,143 asymptomatic control subjects from five independent cohorts (All of Us Research Program, UK Biobank, Bellygenes, Genetic Epidemiology Research on Aging, FinnGen). IBS risk loci were functionally annotated to identify candidate genes. Systematic variant-level analysis, including variants annotation, functional genomics and expression quantitative trait loci, prioritized potential causal variants. Gene-level analyses, including transcriptome-wide association study, colocalization analysis and Mendelian randomization, nominated the potential causal genes.

Results

We identified two independent IBS susceptibility loci at genome-wide significance (P < 5 × 10⁻⁸) in All of Us Research Program cohort totaling 14,897 cases and 245,388 controls. GWAS-meta analysis identified 12 novel independent (P < 5×10^-8) signals and 5 unreported loci (rs143348218, rs3748618, rs6432674, rs9536395, rs976714). Subtype-specific (P < 5×10^-8) findings based on subtype-specific GWAS meta-datasets included 3 loci for subtype IBS-C (3 novel independent loci) , 44 loci for IBS-M (2 novel independent loci). By integrating evidence from layers of different analyses, we prioritized the most plausible causal genes for IBS including CADM2, PCLO, PHF2 and SHISA6. Notably, PCLO (associated with bipolar disorder and major depressive disorder) and SHISA6 (overexpression in Platelet and T-lymphocyte) have been previously unreported in association with IBS.

Conclusion

Our study not only showed the power of the last large-scale GWAS in deciphering the genetic aetiology of IBS, but also uncovered 5 new genetic risk variants, potential unreported causal variants, genes and therapeutic targets for IBS.

References

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