Evaluation of the Ileo-anal Pouch in FAP (ENDOPOL)

This study is an international, multicentre, randomised controlled trial comparing dye-based chromoendoscopy with virtual chromoendoscopy during surveillance pouchoscopy in adults with familial adenomatous polyposis and an ileal pouch-anal anastomosis. The anticipated study duration is approximately 2 years. Following restorative proctocolectomy, adenomas may develop within the ileal pouch, rectal cuff or pre-pouch ileum. Continued endoscopic surveillance is therefore recommended because progressive adenomatous change may be associated with high-grade dysplasia or malignancy. Current surveillance guidelines permit the use of enhanced endoscopic imaging but do not specify a preferred chromoendoscopy technique because comparative evidence in this setting remains limited. Dye-based chromoendoscopy involves topical application of contrast dye to enhance mucosal surface architecture and lesion margins. Virtual chromoendoscopy uses optical or digital image-enhancement technologies, including narrow-band imaging or blue-light imaging, to improve visualisation of mucosal and vascular patterns without routine application of contrast dye. Both approaches are established in clinical endoscopy, although practice varies between centres. Virtual chromoendoscopy is commonly used at St Mark's Hospital, whereas dye-based chromoendoscopy remains the predominant approach at several other European centres. No adequately powered randomised study has directly compared dye-based and virtual chromoendoscopy for surveillance of an ileal pouch in familial adenomatous polyposis. The relative ability of each technique to identify clinically relevant adenomas, characterise overall polyp burden and support reproducible lesion measurement therefore remains uncertain. The present study is intended to provide comparative evidence, reduce variation in surveillance practice and inform future recommendations regarding the optimal imaging approach. Participant identification and enrolment Potential participants scheduled for clinically indicated surveillance pouchoscopy will be identified by the local clinical team through endoscopy booking systems, polyposis registries or equivalent institutional records. Study information may be provided electronically or by another locally approved method before the planned procedure. Potential participants will have an opportunity to review the study information and raise questions before enrolment. Final confirmation of eligibility and written informed consent will occur before the surveillance procedure. Participation will not alter the clinical indication for pouchoscopy. Declining participation will not affect the scheduled procedure, subsequent care or future surveillance. Randomisation will occur after consent and before insertion of the endoscope. The allocated imaging technique will be used during the diagnostic inspection phase of the pouchoscopy. Randomisation and allocation Randomisation will be performed through Castor Electronic Data Capture using an independent computer-generated allocation sequence. Allocation will occur in a 1:1 ratio between dye-based chromoendoscopy and virtual chromoendoscopy. Variable block sizes of 2, 4 and 6 will be used to preserve allocation balance while reducing the predictability of subsequent assignments. Randomisation will be stratified by participating centre to account for potential centre-level differences in participant characteristics, endoscopy platforms, surveillance practices and procedural technique. The allocation sequence will be concealed within the electronic randomisation system until enrolment and confirmation of eligibility have been completed. Access to the randomisation module will be limited to authorised study personnel at participating centres. Blinding of the endoscopist is not feasible because dye-based and virtual chromoendoscopy have distinct procedural and visual characteristics. Participant blinding may also be impractical when pouchoscopy is performed under no sedation or mild conscious sedation. Histopathological assessment will be undertaken according to local routine practice, with pathological interpretation based on submitted specimens rather than the assigned endoscopic imaging technique. Endoscopic procedure Surveillance pouchoscopy will be performed by endoscopists with experience in familial adenomatous polyposis and ileal pouch surveillance. Procedures will follow local clinical standards and applicable national or European guidance. The examination will include the pre-pouch ileum, pouch body and rectal cuff or retained rectal mucosa. The endoscope will be advanced to the pre-pouch ileum, followed by systematic withdrawal and circumferential mucosal inspection. A spiral withdrawal technique will be encouraged to maximise visualisation of the mucosal surface. Irrigation and suction will be used as required to remove residual debris, mucus or fluid. Retroflexion will be performed within the pouch when considered technically feasible and clinically appropriate, allowing detailed inspection of the rectal cuff, anastomosis and distal pouch. Any limitation affecting mucosal visualisation, including inadequate preparation, retained contents, luminal narrowing, inflammation or technical difficulty, will be documented. Dye-based chromoendoscopy group In the dye-based chromoendoscopy group, the pre-pouch ileum, pouch body and rectal cuff will be examined following topical application of indigo carmine. Dye will be applied through a spray catheter or another standard endoscopic delivery device. Application will be sufficiently diffuse to enhance mucosal topography across the relevant anatomical regions. Additional targeted dye application may be undertaken when an area requires closer inspection. Following dye application, the mucosa will be examined systematically during withdrawal of the endoscope. Indigo carmine functions as a contrast agent by pooling within mucosal grooves and depressions, thereby accentuating surface irregularities and lesion borders. Detection, characterisation and documentation of suspected adenomas will occur during the dye-enhanced inspection phase. Virtual chromoendoscopy group In the virtual chromoendoscopy group, the pre-pouch ileum, pouch body and rectal cuff will be examined using narrow-band imaging, blue-light imaging or an equivalent compatible virtual chromoendoscopy mode available on the endoscopy platform at the participating centre. Virtual chromoendoscopy will be activated during systematic mucosal inspection. White-light imaging may be used for initial orientation, irrigation and identification of anatomical landmarks. The allocated virtual chromoendoscopy mode will then be used for detailed lesion detection and characterisation. Routine indigo carmine application will not be used during the primary diagnostic inspection in this group. Targeted dye application may only be undertaken when required for clinical safety or management after completion of the allocated diagnostic assessment. Any such use will be recorded as a procedural deviation or additional clinical intervention, as appropriate. Lesion detection and documentation All detected lesions will be documented according to anatomical location, estimated size and endoscopic appearance. Location will be recorded separately for the pre-pouch ileum, pouch body and rectal cuff or rectal remnant. Lesion size will be estimated in millimetres. A closed or open biopsy forceps with known dimensions will be used as a visual reference where appropriate. The largest estimated diameter will be recorded. Standardised study guidance will be provided to reduce variability in the measurement of small lesions. Polyp burden will be recorded using study-specific scoring tables. Separate assessments will be completed for the pouch body and rectal cuff, with an additional combined assessment representing overall pouch-related polyp burden. The scoring framework will account for lesion number, lesion size and anatomical distribution. Endoscopic images will be captured for representative lesions and relevant anatomical regions. Images will be obtained in a standardised manner where possible and will include a size reference when technically feasible. Image capture will support central or secondary assessment of lesion size and polyp burden. Lesions with features suspicious for advanced neoplasia will be documented in detail. Relevant features may include irregular morphology, ulceration, spontaneous bleeding, depression, disrupted vascular pattern, marked surface irregularity or a non-lifting appearance. Management of such lesions will follow established clinical practice and local governance arrangements. Endoscopic treatment After completion of the allocated diagnostic inspection and documentation of polyp burden, adenomas meeting criteria for endoscopic treatment will be removed using standard polypectomy techniques. Indications for polypectomy will include: * lesions larger than 5 mm within the pouch body; * lesions larger than 2 mm within the rectal cuff or retained rectal mucosa; and * lesions with endoscopic features suspicious for high-grade dysplasia or early malignancy. Removal techniques may include cold biopsy forceps, cold snare polypectomy, hot snare polypectomy or another clinically appropriate method. Selection of the resection technique will depend on lesion size, morphology, location and local practice. Resected tissue will be retrieved for histopathological examination whenever clinically appropriate. Histological assessment will follow local pathology protocols. Relevant pathological features may include adenomatous histology, grade of dysplasia, completeness of excision where assessable and evidence of invasive malignancy. Clinical management arising from histopathological findings will remain the responsibility of the treating clinical team and will follow local multidisciplinary pathways. Reliability assessment Variation in endoscopic estimation of polyp size and burden may be particularly important for lesions smaller than 5 mm. A structured reliability assessment will therefore be incorporated into the study. Participating endoscopists will assess a standardised set of endoscopic images showing lesions and representative polyp burden. Each assessor will record lesion size and the corresponding polyp-burden category using the study scoring system. The same image set will be reassessed after an interval of approximately 1 week. The order of images may be altered during the repeat assessment to reduce recall effects. Inter-rater reliability will be calculated to quantify agreement between endoscopists. Intra-rater reliability will be calculated to quantify consistency within individual assessors across the two assessment time points. Statistical methods appropriate to the scale and distribution of the measurements will be used, including correlation coefficients, intraclass correlation coefficients or kappa statistics where applicable. The reliability analysis will inform the interpretation of data relating to small adenomas. Lesions smaller than 5 mm will be included in relevant analyses when measurement and classification demonstrate acceptable reproducibility. Sensitivity analyses may be performed using alternative lesion-size thresholds where reliability is insufficient. Procedural quality parameters Standardised quality parameters will be collected for each pouchoscopy. Bowel preparation and mucosal cleanliness will be assessed using an adapted Boston Bowel Preparation Scale suitable for pouchoscopy. Scores will reflect the quality of visualisation within the relevant pouch segments. Additional cleansing performed during the procedure will also be recorded where required by the case report form. Total procedure duration will be recorded. Procedural time will include endoscope insertion, irrigation, suction, dye application in the dye-based chromoendoscopy group, activation and use of virtual chromoendoscopy, systematic mucosal inspection, retroflexion, lesion documentation, polypectomy, specimen retrieval and endoscope withdrawal. Factors affecting procedural duration will be documented where relevant, including extensive polyp burden, difficult anatomy, poor preparation, therapeutic intervention or technical equipment issues. Additional procedural information may include sedation, completeness of examination, depth of insertion into the pre-pouch ileum, use of retroflexion, number of lesions removed, polypectomy technique and immediate adverse events. Post-procedure management Immediate post-procedure care will follow routine clinical practice at each participating centre. Participants will receive standard advice regarding symptoms requiring medical review after pouchoscopy or polypectomy. Potential adverse events may include abdominal pain, bleeding, perforation, post-polypectomy syndrome, sedation-related complications or another clinically significant event. Adverse events identified during the procedure or reported after discharge will be documented and managed according to local clinical pathways and study reporting requirements. Subsequent surveillance pouchoscopy will be scheduled according to local policy, clinical findings, histopathological results and applicable guidelines. The study allocation will not determine the interval to the next surveillance procedure. Data collection and management Study data will be recorded in Castor Electronic Data Capture using standardised electronic case report forms. Each participant will be assigned a unique study identification number. Data entered into the central study database will not include directly identifying information. The participant identification log linking study numbers to local identifiers will remain securely stored at the recruiting centre and accessible only to authorised personnel. Source data will remain within routine clinical systems and study files at each participating institution. Relevant source documentation may include endoscopy reports, pathology reports, procedure records, adverse-event documentation and endoscopic images. Pseudonymised study data will be transferred to the central study team at Amsterdam University Medical Center for data management, pooling and statistical analysis. Data transfer will occur under an applicable data-transfer agreement and in accordance with institutional, national and European data-protection requirements. Database access will be role-based and password-protected. Data validation checks, range checks and query resolution procedures will be used to support completeness and accuracy. Participating centres may be asked to clarify missing, inconsistent or implausible entries. Endoscopic images used for reliability or central review will be pseudonymised before transfer. Image files will not contain names, hospital numbers, dates of birth or other direct identifiers. The final analytical dataset will combine pseudonymised data from participating centres. Statistical analysis will be undertaken according to a prespecified statistical analysis plan. Any protocol deviations affecting allocation, imaging technique, completeness of examination or data integrity will be recorded and considered during analysis.