Inclusion Criteria:

• - CD patients in steroid-free remission for at least 3 months, but no more than 2 years.

• - CDAI < 150.

Exclusion Criteria:

• - Clinical remission for more than 2 years.

• - Patients on a second/third line of biologic class of treatment.

1. Entry procedures: Patients will undergo clinical examination and history taking and then will undergo patency capsule. If patency is proven, patients will undergo a third generation pan-enteric capsule endoscopy (PillCam Crohn), ileocolonoscopy with biopsies (by separate consent), MRE, Intestinal US, biomarkers, immune & microbiome analysis, and health related quality of life assessment and patient reported outcome (PRO) standard questionnaires. (see Appendix 1 for complete protocol of baseline pan-enteric capsule endoscopy and ileocolonoscopy evaluation, Appendix 2 for complete protocol of MRE examination, Appendix 3 for blood and stool sample collection protocols, Appendix 4 for Intestinal US protocol, appendix 5 for microbiomic analysis protocol, appendix 6 for health related quality of life/cost assessments, appendix 7 for Immune analysis). 2. Follow-up procedures: Capsule endoscopy, nutritional and intestinal US studies will be performed every 6 months for the total study duration of 2 years. For patients with only small bowel disease these will be without preparation. Additionally, periodic (every 3 months) assessment will be performed for inflammatory, microbiome, imaging attributes, quality of life and immunophenotyping, as outlined below in description of tasks for work packages. 3. Risk stratification and outcomes: Based on VCE results and according to the predictive algorithm defined by the first project's results, patients will be classified as high risk if having Lewis score (LS) ≥350 for the small bowel tertile with the highest score, or as having low risk (LS<350 highest tertile score) for future relapse of disease. Low risk patients will continue the monitoring scheme and their treatment regimen unaltered. Patients with LS ≥350 will be randomized to either continue follow-up with unaltered therapy or to proactive therapy optimization with TDM assessment. Therapy will be optimized based on the optimization protocol described below, with the aim to prevent flares and complications. Follow up to determine the occurrence of clinical flares and complications as well as the status of inflammatory process will be performed for all patients q3months. Study will be terminated and a patient will be withdrawn upon disease flare or complication or if a change of CD medications was instituted (except for treating verified infectious complication such as C. difficile infection) and such a patient will be considered a non-responder. A patient will also be withdrawn if in the opinion of the Principle Investigator (PI), a new adverse event or medical condition is present that endangers the patient's wellbeing if the study protocol is adhered to. To maintain temporally-restricted blinding, VCE results will be disclosed up to three months following the performance of VCE. * In a sub-group of consenting patients, stool samples for microbiome analysis (see below) will be collected daily for a designated period of time. In a sub-group of consenting patients, additional on-line data collection methods will be employed (see below). Risk-based intervention: Patients meeting the VCE-based high-risk criteria and who were randomized to proactive treatment arm will receive therapy intensification within 30 days. Re-assessment of response to the intensified therapy will be performed by repeated VCE and bio-markers after 6 months. The intensification protocol will be as appears below. Briefly, patients receiving immunomodulators,5-Aminosalicylates (5ASA) or no treatment at the time they are found to have high risk of imminent flare or complication will receive induction with a biologic of the anti-Tumor necrosis Factor (TNF)- Infliximab (IFX), Adalimumab (ADA)- or anti-integrin (VDZ) classes as per standard induction protocols for these agents. The choice of the biologic will be guided by the treating physician's discretion as per the individual patient-related considerations. In patients already on a biologic, intervention will be guided by protocolized TDM results for patients on anti-TNFs, whereas patients receiving vedolizumab will first receive an interval-halving intervention. Protocolized anti-TNF TDM-based intervention will comprise of increasing the dose of anti-TNF, or switching anti-TNF, or switching out-of-class according to the drug/anti-drug antibodies thresholds and algorithms set by previous works by our group in this field, using the same assay that will be employed in the present trial. Re-adjustment of therapy according to these principles will be performed if 6-month VCE re-assessment does not show a reduction of patient risk score to the range of a low risk VCE-based score. Patients who received an intervention and in whom follow-up 6 months VCE does not show a reduction of 225 points on the Lewis score or highest segment Lewis score of <350, will receive the next protocolized drug optimization. Intervention protocol in proactive arm based on current treatment and TDM finding: ADL with drug level<8mcg/ml/AAA<4mcg/ml-eq ADL dose-doubling ADL with drug level <8mcg/ml/AAA>4mcg/ml-eq Switch anti TNF or add IMM ADL with drug level >8mcg/ml Switch out of class IFX with drug level <6mcg/ml/ATI<9mcg/ml-eq IFX dose-doubling IFX with drug level <6mcg/ml/ATI>9mcg/ml-eq Switch anti TNF or add IMM IFX with drug level >6mcg/ml Switch out of class VDZ e/8 week VDZ interval halving VDZ e4W/CD3CD45RO target occupied >85% Switch out of class VDZ e4W/ CD3CD45RO target occupied<85% VDZ double-dosing 600/4w UST 90mg/SC e12w or e/8W Shorten interval e/4w No treatment, 5-ASA or AZA/6MP >> Start biologic ADL - adalimumab, IFX- infliximab, VDZ - vedolizumab UST - Ustekinumab AAA- antibodies to adalimumab, ATI antibodies to infliximab, IMM - immunomodulator

Arms

Interventions