C0365 - Symptoms and Laboratory Values as Proxies for Endoscopic and Histologic Clinical Endpoints in Ulcerative Colitis: A Mediation Analysis Based on Upadacitinib Phase 3 Induction Trials

Introduction: We evaluate the extent to which commonly available measures in clinical practice (i.e., signs, symptoms, and laboratory values) mediate endoscopy-based clinical measures.

Methods: We analyzed, in the intent-to-treat population from upadacitinib’s (UPA) phase 3 induction trials (U-ACHIEVE Induction, U-ACCOMPLISH in moderately to severely active UC, relationships between deep mucosal healing (DMH), histologic endoscopic mucosal improvement (HEMI), and change from baseline in endoscopic score as outcomes, and signs/symptoms and lab values as mediators (fecal calprotectin, high sensitivity C-reactive protein [hs-CRP], abdominal pain [AP], bowel urgency [BU], and Partial Adapted Mayo Score [PA-Mayo]). The mediated proportion of effect at week (wk) 8 was calculated as the difference in mean outcomes due to a one-unit change in mediators while controlling for baseline characteristics.The effects of mediators at wks 2 and 8 were assessed. Analyses assumed mediators were unrelated to each other and used linear models for all variables. Missing values for DMH and HEMI at wk 8 were imputed via non-responder imputation per trial protocol, while other variables were analyzed as-observed. Standard errors were computed via bootstrap.

Results: A total of 878 patients were included; mean (standard deviation [SD]) age was 42.9 (14.4) years and disease duration was 8.0 (7.2) years. At wk 8, 9.0% of patients achieved DMH and 25.7% achieved HEMI, and mean (SD) change from baseline of the endoscopic score was -0.70 (0.97). All outcomes were mediated by PA-Mayo and BU (Table 1). PA-Mayo mediated around a third of the total effect for all outcomes with similar mediation at wk 2 and 8 (all P< 0.05). The proportion mediated by BU was larger at wk 8 and ranged from one to two thirds of the total effect (all P< 0.05 except for wk 2 for DMH). In contrast, hs-CRP at wk 2 only mediated 2-3% across outcomes (all P< 0.05). The predictive power of the models was similar using wk 2 and 8 mediators and explained 15% (DMH), 40% (HEMI), and 50% (endoscopic score) of variation.

Discussion: Our study found that easily accessible measures such as Partial Adapted Mayo Score and bowel urgency can mediate endoscopy-based endpoints for UC as early as wk 2 of induction, with mediation effects persisting for concurrently assessed signs and symptoms. Our findings suggests that symptom-based measures for UC in clinical practice could be useful proxies for endoscopic and histologic outcomes.