OP02Efficacy and safety of vedolizumab combined with upadacitinib as an 8-week induction strategy in moderate-to-severe ulcerative colitis: a multicenter, randomized controlled trial

Background Advanced monotherapies for ulcerative colitis (UC) face an ‘efficacy ceiling’ (approx. 30% induction remission). We evaluated a ‘hit-hard-and-early’ strategy combining potent, rapid upadacitinib (UPA) for induction with gut-selective, safe vedolizumab (VDZ). This addresses a key AGA guideline knowledge gap, testing if 8-week UPA+VDZ induction is superior to VDZ monotherapy. Methods In a prospective, multicenter, randomized, open-label trial, adults with moderate-to-severe UC (modified Mayo 4-9, MES≥2) were randomized 1:2 to combination (VDZ 300mg IV wks 0,2,6 + UPA 45mg PO daily for 8 wks) or VDZ monotherapy (VDZ 300mg IV wks 0,2,6). The primary endpoint was endoscopic remission (MES=0) at week 8 by blinded central reading. Key secondary endpoints included week 8 clinical remission and histologic-endoscopic mucosal improvement (HEMI). Analysis was mITT. (NCT06095596). Results The mITT population included 113 patients (40 combination, 73 monotherapy); baselines were balanced. The primary endpoint of endoscopic remission (MES=0) at week 8 was met: 37.5% (15/40) in combination vs 15.1% (11/73) in monotherapy (absolute risk difference 22.4%; 95% CI, 5.3-39.5; P = 0.007; adjusted OR 3.34; 95% CI, 1.34-8.58). Combination therapy was also superior for clinical remission (66.7% vs 40.0%; P = 0.013) and HEMI (45.7% vs 17.7%; adjusted OR 3.58; 95% CI, 1.41-9.41; P = 0.008). Adverse events during the 8-week induction were comparable (7.5% vs 7.0%; P > 0.9), with no serious adverse events reported. Conclusion Eight-week combined UPA+VDZ induction was superior to VDZ monotherapy for achieving early endoscopic, clinical, and histologic-endoscopic remission in moderate-to-severe UC, with a comparable short-term safety profile. This study provides the first randomized evidence for this sequential ‘hit-hard-and-early’ strategy, suggesting a new paradigm to overcome the therapeutic ceiling in UC. References: 1.Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet 2023;402:571-584. 2.Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol 2015;12:720-7. 3.Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017;390:2769-2778. 4.Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol 2019;114:384-413. 5.Wangchuk P, Yeshi K, Loukas A. Ulcerative colitis: clinical biomarkers, therapeutic targets, and emerging treatments. Trends Pharmacol Sci 2024;45:892-903. 6.Ardizzone S, Cassinotti A, Duca P, et al. Mucosal healing predicts late outcomes after the first course of corticosteroids for newly diagnosed ulcerative colitis. Clin Gastroenterol Hepatol 2011;9:483-489.e3. 7.Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021;160:1570-1583. Conflict of interest: Wu, Hongzhen: No conflict of interest Wu, Luying: No conflict of interest Xie, Tingting: No conflict of interest Wu, Ji: No conflict of interest Chen, Huangwei: No conflict of interest Yu, Qiao: No conflict of interest Cao, Xiaocang: No conflict of interest Zhi, Min: No conflict of interest Yao, Jiayin: No conflict of interest