ENDOSCOPIC SCORE INTER-READER CONCORDANCE ANALYSIS FROM A PHASE 2B STUDY IN PATIENTS WITH MILD-TO-MODERATE UC

Abstract BACKGROUND Endoscopic assessment of disease severity is a key component of ulcerative colitis (UC) clinical studies. However, interobserver variability may contribute to bias in selecting study candidates and evaluating response rates. Scoring by blinded central readers has become the recommended standard method of assessment to minimize bias and interobserver variance. We present concordance rates between central and local readings from a Phase 2b study of investigational microbiome therapeutic SER-287 in patients with mild-to-moderate UC. METHODS This double-blind, placebo-controlled study screened 494 and randomized 203 adults (51.7% male; mean age 45.6 years; 83.7% white) 1:1:1 to 3 arms (Figure 1). Active UC was defined as ≥15 cm disease from the anal verge, a Three-Component Modified Mayo Score of 3-7, endoscopic subscore (ES) ≥1, and stool frequency subscore ≥1. Endoscopy was performed at screening, after induction, after exploratory maintenance or open-label, and for flare assessments. Endoscopic videos were scored by each site’s gastroenterologist (local ES), and by any 1 of 4 blinded central readers (Alimentiv; Ontario), with adjudication by a 2nd blinded central reader (Alimentiv), if necessary. If all 3 scores were discordant, the median score was designated as the final ES. Concordance between local and central readers were analyzed by timepoint and in total and quantified using weighted kappa statistics. RESULTS Concordance analyses were conducted for 608 ES comparisons between local and the 1st central reader (Local vs Central1 [LvC1]), and 337 comparisons where adjudication was necessary (Local vs Central2 [LvC2]; Central1 vs Central2 [C1vC2]). Observed concordance rates were: -LvC1: 44% (271/608, kappa = 0.61, Figure 2); -LvC2: 26% (86/337, kappa = 0.46); -C1vC2: 64% (216/337, kappa = 0.74). Concordance rates were comparable across study periods: -Screening: -LvC1: 42% (131/310, kappa = 0.59) -LvC2: 27% (48/179, kappa = 0.48) -C1vC2: 66% (118/179, kappa = 0.76) -Week 11: -LvC1: 46% (79/170, kappa = 0.61) -LvC2: 25% (22/91, kappa = 0.46) -C1vC2: 62% (56/91, kappa = 0.75) Local readers scored lower than C1 readers in 274/337 (81%) discordant cases (Figure 2), and lower than C2 in 221/251 (88%) discordant cases. The most frequent sources of discordance were L=ES2 vs C1=ES3 (153 videos) and L=ES1 vs C1=ES2 (77 videos). CONCLUSIONS In this Phase 2b study, low ES concordance highlights marked interobserver variability between local and blinded central readers. Local scores were consistently lower than central scores across all study time points. Despite low concordance rates, efficacy conclusions remain unchanged if only local ES scores were used for endpoint assessments. Objective, standardized, and consistent methods for evaluating ES are needed to better quantify disease severity and the impact of UC therapies.

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