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

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

Immune checkpoint inhibitors (ICIs) have marked a breakthrough in the management of a wide range of cancer types, leading to increased overall survival. However, this treatment is frequently associated with the onset of various immune-related adverse events (irAEs), including ICI-related diarrhea and colitis.¹ Current recommendations for patients with diarrhea or colitis grade 2 or higher (graded via CTCAE)² include the discontinuation of ICI and administration of immune suppressants (e.g. steroids or biologics), which may lead to worse outcomes in these patients.³ Therefore, alternative therapeutic strategies to manage irAEs are needed. The gut microbiota plays a pivotal role in the onset of gastrointestinal irAEs, but the role of its therapeutic modulation on these disorders is mostly unknown. ^4,5

Aims & Methods

Our aim was to evaluate the efficacy and safety of therapeutic microbiome modulation for gastrointestinal irAEs in cancer patients. We enrolled cancer patients affected by ICI-related diarrhea/colitis referred to our Microbiome Clinic from January 2023 to March 2025. After clinical evaluation, patients were stratified according to severity of diarrhea (graded via CTCAE)² and then received a microbiome-modulating therapy. Patients were followed-up for at least 8 week after the initiation of therapy. We collected data about patient demographics (age and gender), patient’s overall health status as assessed by the the Charlson Comorbidity Index (CCI)⁶, type of cancer, oncological therapy and its suspension, time in weeks from initiation of cancer therapy to onset of diarrhea, severity of diarrhea (graded via CTCAE)², time in weeks until resolution of diarrhea and resumption of oncological therapy

Results

We enrolled 42 patients in the study period (8 males, 34 females, mean age 58,3 years-old, mean CCI-index 5.8). All patients were treated with ICI (Pembrolizumab: n=25 , Dostarlimab: n=4, Nivolumab: n=4; Atezolizumab: n=3; Novulumab and Ipilumab: n=2, Cemiplimab: n=2; Mogamulizumab: n=1; Pertuzumab: n=1). Ten patients experienced G1 diarrhea (23,8%), 16 (38,1) G2, 15 (35,7%) G3 and one G4 (2,4%). As indicated by current European Guidelines³, 30 patients (71,4%) had to interrupt ICI due to diarrhea. Multi-strain probiotics were administered to 27 (64.3% ) patients, rifaximin to 22 (52,4%). Overall, 21 patients (50%) needed therapy with systemic steroids. Seven patients who experienced ICI-related colitis refractory to steroids and biologics were successfully treated with FMT. Twenty-eight patients (66.7% ) had a resolution of the diarrhea (G0) and 11 patients (26.2%) had diarrhea G1 at a mean time of 8 weeks. Upon resolution of diarrhea, nine of the 30 patients who had interrupted ICI (30%) were able to resume the treatment. None of the patients experienced any adverse event related to gut microbiota modulation as defined by CTCAE².

Conclusion

Therapeutic modulation of gut microbiota appears to be a promising safe and effective approach for treating ICI-related diarrhea and colitis. However, these preliminary findings need confirmation through more consolidated and well-designed studies.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009
3. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
4. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
5. Wang T, Zheng N, Luo Q, et al. Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.01235
6. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.