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Background The PIONIR (Preventing IBD ONset in Individuals at Risk) trial evaluates whether the Tasty&Healthy diet can reduce risk of Crohn’s disease (CD) development in first-degree relatives (FDRs). The optimal preclinical stage of CD for enrolling subjects to prevention trials is unknown.Objectives We aimed to propose a framework for identifying high-risk participants for prevention trials by reporting the outcomes of the pre-PIONIR screening stage.Design Faecal calprotectin was measured in asymptomatic FDRs aged 6–38 years; those with persistent elevation, defined as >70 µg/g in at least two separate tests, were offered panenteric video capsule-endoscopy or ileocolonoscopy.Results Of 950 FDRs approached, 331 (35%) agreed to be screened: 63 (19%) had persistently elevated calprotectin, of whom 42 underwent further evaluation. Nine (2.7%) had endoscopic appearance compatible with presymptomatic CD, 22 (6.6%) had non-specific macroscopic mucosal changes and 11 (3.3%) had normal mucosa despite elevated calprotectin, suggesting probable histological inflammation. The 33 participants in the two latter groups were defined as ‘potential pre-CD’ (17.9% of all screened after adjusting for missing values). Calprotectin >225 µg/g predicted presymptomatic CD (area under the receiver operating characteristic curve 0.97 (95% CI 0.94 to 1.0; p<0.001; sensitivity 89%, specificity 94%). Of those with a single elevated calprotectin value, 22% normalised on repeat testing with significant variability (intraclass correlation coefficient 0.72 (95% CI 0.57 to 0.82)).Conclusion Approximately one in five asymptomatic FDRs had persistently elevated calprotectin, which was able to differentiate those with presymptomatic CD. The findings highlight calprotectin’s utility in identifying at-risk individuals during the potential pre-CD stage for enrolment in prevention trials.