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A prospective randomized three-arms controlled trial of Crohn's Disease (CD) patients in remission of <24 months duration. Patients will undergo screening by Magnetic Resonance Enterography (MRE) and patency capsule, and (if agreeing by separate consent) a baseline colonoscopy. Patients in whom patency of small bowel is proven will undergo video-capsule using the dedicated Inflammatory-Bowel Disease (IBD)-capsule (PillCam Crohn's). Patients with Lewis score>350 for worst small bowel segment will be classified as high-risk and will be randomized for continued standard treatment or proactive treatment. Proactive treatment will consist of escalating/switching biologic treatment according to the pre-defined therapeutic drug monitoring (TDM)-based treatment-intensification protocol, or will consist of initiating biologic therapy in high-risk patients not receiving biologics at the time of enrollment. Both high-risk patients arms - the continued standard treatment and the proactive arm - will be followed up by clinic visits with physical examination, inflammatory and immune markers' assessment and microbiome analysis every 3 months and by serial video-capsule endoscopy (VCE) studies+ intestinal UltraSound (US) every six months. Patients who are classified as low-risk patients, as per Lewis score<350 at baseline, will continue standard treatment and be similarly followed. All enrolled patients will undergo MRE at the end of the trial. All patients will undergo in addition blood and stool sampling for inflammatory markers, immune-phenotyping and microbiome analysis. All patients will undergo MRE at the end of the trial.
Full description
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 Study will be terminated and a patient will be withdrawn upon disease flare or complication or if a change of CD medications was instituted (except for treating verified infectious complication such as C. difficile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
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60 participants in 3 patient groups
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Limor Selinger; Abraham Eliakim, Prof.
Data sourced from clinicaltrials.gov
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