AbstractAimTreatment pathways for significant rectal polyps differ depending on the underlying pathology, but pre‐excision profiling is imperfect. It has been demonstrated that differences in fluorescence perfusion signals following injection of indocyanine green (ICG) can be analysed mathematically and, with the assistance of artificial intelligence (AI), used to classify tumours endoscopically as benign or malignant. This study aims to validate this method of characterization across multiple clinical sites regarding its generalizability, usability and accuracy while developing clinical‐grade software to enable it to become a useful method.MethodsThe CLASSICA study is a prospective, unblinded multicentre European observational study aimed to validate the use of AI analysis of ICG fluorescence for intra‐operative tissue characterization. Six hundred patients undergoing transanal endoscopic evaluation of significant rectal polyps and tumours will be enrolled in at least five clinical sites across the European Union over a 4‐year period. Video recordings will be analysed regarding dynamic fluorescence patterns centrally as software is developed to enable analysis with automatic classification to happen locally. AI‐based classification and subsequently guided intervention will be compared with the current standard of care including biopsies, final specimen pathology and patient outcomes.DiscussionCLASSICA will validate the use of AI in the analysis of ICG fluorescence for the purposes of classifying significant rectal polyps and tumours endoscopically. Follow‐on studies will compare AI‐guided targeted biopsy or, indeed, AI characterization alone with traditional biopsy and AI‐guided local excision versus traditional excision with regard to marginal clearance and recurrence.