P900 A PROOF-OF-CONCEPT, PLACEBO-RANDOMIZED CONTROLLED TRIAL TARGETING ADHERENT AND INVASIVE ESCHERICHIA COLI (AIEC) WITH ANTIBIOTICS IN CROHN’S DISEASE: the TEOREM TRIAL

Abstract

Abstract Background Adherent-invasive E. coli (AIEC) are found in the ileal mucosa of 21-63% of patients with ileal Crohn’s disease (CD) vs 0-16% of controls. This trial tested the efficacy of antibiotics targeting AIEC in CD patients with ileal involvement, colonized by AIEC. Methods Eligible patients had endoscopically active (CDEIS ≥8) ileal or ileocolonic CD and either a clinically inactive, or mild to moderately active disease that responded to budesonide or prednisolone. AIEC search was performed on ileal biopsies, by phenotypical assays. The primary endpoint was the endoscopic overall response at week 12, defined as segmental response in at least 1 segment, and < 20% increase of CDEIS in other segments. Segmental response was defined by decrease ≥ 50% of surface of ulcerations, or loss of deep ulcerations (if any). Secondary endpoints were ΔCDEIS ≥ 50% in at least 1 segment with CDEIS ≥ 8 at baseline, and remission (CDEIS < 6 in all segments). Endoscopic endpoints were assessed by a central, anonymous and blinded scoring of video recordings of colonoscopies at preinclusion and week 12. Patients were randomized 1/1 between oral Ciprofloxacin 500 mg bid + Rifaximin 800 mg bid and double placebo for 12 weeks. In this subgroup of patients selected for AIEC colonization, we were in search of a strong signal of efficacy. We hypothesized that 60% of patients in the experimental arm and 25% of those in the placebo arm would reach the primary endpoint. 31 patients in each arm were planned to demonstrate such a difference. Results Between May 2016 and June 2021, 155 patients were screened, of whom 91; 27 were AIEC positive and 24 patients (12 in each arm) were randomized in 10 centres. 17 patients had a clinically active disease. All AIEC strains of randomized patients were sensitive to ciprofloxacin and rifaximin. Clinical and endoscopic characteristics were similar in the 2 arms. 2 patients did not have colonoscopy at week 12 (1 tendinitis and 1 had no colonoscopy during the COVID pandemic). 7/10 patients cleared AIEC at week 12 in the experimental arm, vs 6/12 in the placebo arm. The 3 patients who received antibiotics and remained AIEC+ after antibiotics acquired resistance to ciprofloxacine. Results are displayed in the table. There was no association between AIEC clearance and endoscopic endpoints. A Bayesian, post hoc analysis showed that the probability to obtain a 35% difference in the primary endpoint between the two arms of the trial was of 25%. Conclusion Antibiotics were not statistically superior to placebo to achieve endoscopic response and remission in patients with ileal CD colonized with AIEC. There was no association between AIEC clearance and endoscopic endpoints. Differences were numerically in favour of antibiotics.