Crohn's disease (CD) (> 200,000 patients in France) is a chronic inflammatory disease that can lead to progression of intestinal destruction and impaired quality of life. Despite the widespread use of biotherapies, intestinal resections remain frequent (50% of patients over time). Unfortunately, surgery is not curative since 75% of patients experienced post-endoscopic operative recurrence (POR) (i.e., recurrence of ulcerations) during the first year after surgery. Prevention of endoscopic POR (defined as a Rutgeerts index ≥ i2) is essential because endoscopic POR is highly predictive of clinical POR (i.e., recurrence of CD-related symptoms): > 40% and > 80% within 5 years for a Rutgeerts index ≥ i2 or ≥ i3, respectively. The recommended management is to start treatment after surgery to avoid endoscopic POR, and to perform a colonoscopy at 6 months (M6) with therapeutic escalation if endoscopic POR. Despite anti-TNF or ustekinumab treatment, the endoscopic POR rate remains high (30-40% at M6) leading to > 40% clinical POR despite therapeutic escalation (90 mg/4 weeks with ustekinumab) potentially due to late therapeutic escalation. Innovative strategies are therefore needed to prevent endoscopic POR, such as the use of fecal calprotectin, a non-invasive biomarker associated with endoscopic CD activity. We have previously demonstrated that its variation between surgery and M3 allows for a value at M3 predictive of endoscopic POR at M6. In this study, we hypothesize, for the first time, that a strategy integrating fecal calprotectin measurement at M3 with earlier therapeutic escalation (M3 vs M6) in case of abnormal value or kinetics could decrease the rate of endoscopic POR at M6.

This is a prospective, open-label, multicenter, randomized, controlled clinical trial with two parallel arms evaluating an innovative approach to standard care in patients with Crohn's disease. All eligible patients will be offered the study consecutively by the principal investigator or any other co-investigator declared for the study.

During the pre-inclusion visit (weeks -4 to -0 before inclusion), after verification of inclusion and exclusion criteria and obtaining informed consent, blood tests and an abdominal ultrasound (if participating in the DESTINY-echo ancillary study) will be ordered (pre-biotherapy assessment, CRP) as well as a fecal calprotectin test.

After re-verification of inclusion and exclusion criteria, at the inclusion visit (V0), patients will be randomized to the two study arms (standard arm vs. active arm). Randomization will be stratified by center and number of risk factors. The outcome of this randomization will be known to both the investigator and the patient.

The reference arm will be based on daily practice, i.e., regular follow-up (weeks 0 and 24) with fecal calprotectin measurement at week 10.

Each patient will be seen with a stool sample at weeks 0, 10, and 24. However, the results will only be provided for patients in the active arm. The fecal calprotectin measurement result at week 10 for patients in the standard arm will not be known during the study but may be disclosed upon patient completion of the study.

Stool samples will be transferred to the biochemistry laboratory at Clermont-Ferrand University Hospital under conditions adapted for the centralized measurement of fecal calprotectin levels (blinded to clinical data). In the active arm, if a fecal calprotectin measurement is abnormal (> 100 µg/g at week 10 or a variation between weeks 0 and 10 > 50 µg/g), the investigator will be notified by an electronic alert, and therapeutic intensification will be implemented at week 12. Fecal calprotectin measurement will be standardized and performed using the same test in all patients. All colonoscopies will be performed and videotaped for both arms at week 24. They will be centrally analyzed by two independent experts, blinded to the strategy, and scored according to the Rutgeerts index to determine the presence of postoperative endoscopic recurrence.

At the end of the study, the patient will be treated and monitored according to current recommendations and at the investigator's discretion.

Inclusion Criteria:

• Patients with an established diagnosis of CD according to ECCO guidelines
• Adult Crohn's disease (age ≥ 18 years)
• Having undergone ileal, colonic, or ileocolonic resection without residual macroscopic lesions
• With an anastomosis that can be reached by ileocolonoscopy
• With at least one of the following risk factors for endoscopic POR: active smoking, previous intestinal resection (before the current resection), length of resected small bowel > 30 cm, fistulizing phenotype (B3 according to the Montreal classification), exposure to at least two biotherapies before surgery
• No contraindication to ustekinumab treatment
• Patient capable of giving consent
• Patient covered by the French healthcare system

Exclusion Criteria:

• Permanent stoma
• Total colectomy
• Uncontrolled postoperative infectious complication
• Pregnant or breastfeeding women: a pregnancy test will be performed for women of childbearing age
• Refusal to participate in the study
• Persons deprived of their liberty by judicial or administrative decision
• Minors
• Vulnerable protected adults (under guardianship, curatorship, or legal protection)