Abstract Background Some patients with inflammatory bowel disease (IBD) do not respond to multiple advanced therapies, resulting in off-label use of two advanced therapeutic agents, known as advanced combination treatment (ACT) (1). Methods This multi-center study in 9 Canadian centers included adult IBD patients treated with either two biological therapies, a biological plus an oral small molecule, or two small molecules. The indication for ACT was characterized as: 1) refractory IBD; 2) concomitant uncontrolled IMID; 3) concomitant uncontrolled EIMs. Primary outcomes were cumulative rates of clinical and endoscopic response and remission at 12 months. Clinical activity was assessed using physician global assessments for both IBD and the concomitant IMID/EIMs. Secondary outcomes included serious adverse events and infections. Cox-proportional hazard analyses identified independent predictors of treatment effectiveness. Multivariate Imputation by Chained Equations accounted for missing data. Results We included 105 IBD patients (76 CD, 29 UC), median age 35 years (IQR 35.4-40.8). At baseline, 39% had perianal involvement, and 58% had failed at least 3 advanced therapies. Most patients (61%) had moderate to severe disease activity, and 40% had prior surgery. The cohort was categorized into three groups based on the rationale for ACT: 63.8% (67/105) received ACT for refractory IBD, 28.8% (30/105) for concomitant IMID, and 7.6% (8/105) for concomitant EIMs. The primary reason for ACT was refractory IBD (63.8%), with the add-on approach used in 97.1% combinations. The most frequent combination was anti-TNF + anti-integrin, followed by the combination of anti-IL-(12)/23 agent + anti-integrin. At 12 months, the cumulative rates of clinical and endoscopic response were 60% and 32.4%, respectively. Cumulative clinical and endoscopic remission rates were 29.5% and 28.6%, respectively (Table 1). Multivariate analysis showed perianal disease was associated with reduced chances of both clinical remission (HR = 0.33, p=0.001), and endoscopic remission (HR = 0.42, p=0.0001) (Table 2). Longer disease duration (HR = 0.96, p = 0.035), baseline moderate-severe disease (HR = 0.41, p = 0.026), and baseline steroid use (HR = 0.39, p = 0.006) were associated with a reduced likelihood of clinical remission. Serious adverse events and infections were reported in 12.4% and 7.6% of patients, respectively. Among serious infections, 5 (62.5%) required hospitalization, 3 (37.5%) were reported as important medical events, and none was life-threatening. Conclusion In this large real-world cohort, ACT was effective in achieving clinical and endoscopic outcomes in patients with refractory IBD or concomitant IMID/EIMs. ACT was well-tolerated, with a favorable safety profile. References 1. Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022 Dec;71(12):2380-2387. doi: 10.1136/gutjnl-2022-327025. Epub 2022 Jun 14. PMID: 35701092.